Thiadiazole analogs thereof and methods for treating smn-deficiency-related-conditions

ABSTRACT

The present invention provides a compound of Formula (X) or a pharmaceutically acceptable salt thereof; 
     
       
         
         
             
             
         
       
     
     a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

BACKGROUND OF THE INVENTION

Proximal spinal muscular atrophy (SMA) is an inherited, clinicallyheterogeneous group of neuromuscular disorders characterized bydegeneration of the anterior horn cells of the spinal cord. Patientssuffer from symmetrical weakness of trunk and limb muscles, the legsbeing more affected than the arms and the proximal muscles weaker thanthe distal ones; diaphragm, facial and ocular muscles are spared. Thereare three forms of childhood-onset SMA (types I, II and III), and arelatively recently categorized adult-onset form IV, all of which can bedistinguished on the basis of age of onset and severity of the clinicalcourse assessed by clinical examination, muscle biopsy andelectromyography (EMG)(Munsat T L, Davies K E (1992)).

Type I (Werdnig-Hoffmann disease) is the most acute and severe form,with onset before six months and death usually before two years;children are never able to sit without support.

Symptoms of the disease can be present in utero, as reduction of fetalmovements; at birth; or more often, within the first four months oflife. Affected infants are particularly floppy, experience feedingdifficulties and diaphragmatic breathing, and are characterized by ageneral weakness in the intercostals and accessory respiratory muscles.Affected children never sit or stand and usually die before the age of2; death is generally due to respiratory insufficiency.

Type II (intermediate, chronic form) has onset between six and eighteenmonths of age; muscular fasciculations are common, and tendon reflexesprogressively reduce. Children are unable to stand or walk without aid.Feeding and swallowing problems are not usually present in Type II SMA,although in some patients a feeding tube may become necessary. Mostpatients generally develop a progressive muscular scoliosis which canrequire surgical correction. Like patients with type I disease, clearingof tracheal secretions and coughing might become difficult because ofpoor bulbar function and weak intercostal muscles. These patients haveprofound hypotonia, symmetrical flaccid paralysis, and no control ofhead movement.

Type III (Kugelberg-Welander disease, or Juvenile Spinal MuscularAtrophy) is a mild, chronic form, with onset after the age of 18 months;motor milestones achievement is normal, and deambulation can bepreserved until variable ages. These patients often develop scoliosis,and symptoms of joint overuse, generally caused by weakness, arefrequently seen. Life expectancy is almost normal but quality of life ismarkedly compromised.

Types I, II and III SMA progress over time, accompanied by deteriorationof the patient's condition.

Adult-onset type IV is characterized by weakness in the second or thirddecade of life, with mild motor impairment not accompanied byrespiratory or nutritional problems. Adult SMA is characterized byinsidious onset and very slow progression. The bulbar muscles are rarelyaffected in Type IV. It is not clear that Type IV SMA is etiologicallyrelated to the Type I-III forms.

Other forms of spinal muscular atrophy include X-linked disease, spinalmuscular atrophy with respiratory distress (SMARD), spinal and bulbarmuscular atrophy (Kennedy's disease, or Bulbo-Spinal Muscular Atrophy),and distal spinal muscular atrophy.

SMA is due to mutations in the Survival of Motor Neuron (SMN) gene,which exists in two forms in humans (SMN1 and SMN2). Loss of SMN isdeleterious to motor neurons and results in neuromuscular insufficiency,a hallmark of the disease. From a genetic point of view, SMA is anautosomal recessive condition, caused by disruption of SMN1 gene,located in 5q13 (Lefebvre S., et al. (1995) Cell 80: 155-165). More than98% of patients with spinal muscular atrophy have a homozygousdisruption of SMN1 by deletion, rearrangement, or mutation. All thesepatients, however, retain at least one copy of SMN2.

At the genomic level, only five nucleotides have been found thatdifferentiate the SMN1 gene from the SMN2 gene. Furthermore, the twogenes produce identical mRNAs, except for a silent nucleotide change inexon 7, i.e., a C-T change six base pairs inside exon 7 in SMN2. Thismutation modulates the activity of an exon splicing enhancer (Lorson andAndrophy (2000) Hum. Mol. Genet. 9:259-265). The result of this and theother nucleotide changes in the intronic and promoter regions is thatmost SMN2 are alternatively spliced, and their transcripts lack exons 3,5, or 7. In contrast, the mRNA transcribed from the SMN1 gene isgenerally a full-length mRNA with only a small fraction of itstranscripts spliced to remove exon 3, 5, or 7 (Gennarelli et al. (1995)Biochem. Biophys. Res. Commun. 213:342-348; Jong et al. (2000) J.Neurol. Sci. 173:147-153). All SMA subjects have at least one, andgenerally two to four copies of the SMN2 gene, which encodes the sameprotein as SMN1; however, the SMN2 gene produces predominantly truncatedprotein (SMNΔ7) and only low levels of full-length SMN protein.

The SMNΔ7 protein is non-functional and thought to be rapidly degraded.About 10% of SMN2 pre-mRNA is properly spliced and subsequentlytranslated into full length SMN protein (FL-SMN), and the rest being theSMNΔ7 copy. The efficiency of SMN2 splicing might be dependent onseverity of disease, and production of a full length transcript of SMN2could range from 10% to 50%. Furthermore, presence or absence of theSMN1 gene, roughly 90% of which becomes the FL-SMN gene product andprotein, influences the severity of SMA by whether or not it cancompensate for the truncated SMNΔ7 copies. A low level of SMN proteinallows embryonic development, but is not sufficient to sustain thesurvival of motor neurons of the spinal cord.

The clinical severity of SMA patients inversely correlates with thenumber of SMN2 genes and with the level of functional SMN proteinproduced (Lorson C L, et al. (1999) PNAS; 96:6307-6311)(Vitali T. et al.(1999) Hum Mol Genet; 8:2525-2532)(Brahe C. (2000) Neuromusc. Disord.;10:274-275)(Feldkotter M, et al. (2002) Am J Hum Genet;70:358-368)(Lefebvre S, et al. (1997) Nature Genet; 16:265-269)(CoovertD D, et al. (1997) Hum Mol Genet; 6:1205-1214)(Patrizi A L, et al.(1999) Eur J Hum Genet; 7:301-309).

Current therapeutic strategies for SMA are mostly centered on elevatingfull length (wild type) SMN protein levels, modulating splicing towardsexon 7 inclusion, stabilizing the wild type protein, and to a lesserextent, on restoring muscle function in SMA by providing trophic supportor by inhibiting skeletal muscle atrophy.

The mechanism leading to motorneuron loss and to muscular atrophy stillremains obscure, although the availability of animal models of thedisease is rapidly increasing knowledge in this field (Frugier T, et al.(2000) Hum Mol. Genet. 9:849-58; Monani U R, et al. (2000) Hum Mol Genet9:333-9; Hsieh-Li H M, et al. (2000) Nat Genet 24:66-70; Jablonka S, etal. (2000) Hum Mol. Genet. 9:341-6). Also the function of SMN protein isstill partially unknown, and studies indicate that it can be involved inmRNA metabolism (Meister G, et al. (2002). Trends Cell Biol. 12:472-8;Pellizzoni L, et al. (2002). Science. 298: 1775-9), and probably intransport of proteins/mRNA to neuromuscular junctions (Ci-fuentes-DiazC, et al. (2002) Hum Mol. Genet. 11: 1439-47; Chan Y B, et al. (2003)Hum Mol. Genet. 12:1367-76; McWhorter M L, et al. (2003) J. Cell Biol.162:919-31; Rossoll W, et al. (2003) J. Cell Biol. 163:801-812).

In addition to the SMAs, a subclass of neurogenic-type arthrogryposismultiplex congenita (congenital AMC) has separately been reported toinvolve SMN1 gene deletion, suggesting that some degree of pathology inthose afflicted is likely due to low levels of motor neuron SMN. (L.Burgien et al., (1996) J. Clin. Invest. 98(5):1130-32. Congenital AMCaffects humans and animals, e.g., horses, cattle, sheep, goats, pigs,dogs, and cats. (M. Longeri et al., (2003) Genet. Sel. Evol.35:S167-S175). Also, the risk of development or the severity ofamyotrophic lateral sclerosis (ALS) has been found to be correlated withlow levels of motor neuron SMN.

There is no cure or effective treatment for SMA available to date andtherefore it would be advantageous to provide novel methods formodulating SMN in order to treat those afflicted with SMA, withneurogenic congenital AMC, ALS, or with other SMN-deficiency-relatedconditions. It would further be advantageous to provide novel drugtargets that could be used as a basis for developing effectivetherapeutics or diagnostics for such neuronal conditions.

SUMMARY OF THE INVENTION

There is a need for new treatments and therapies for Spinal MuscularAtrophy. The invention provides compounds, salts thereof, pharmaceuticalformulations thereof and combinations thereof which compounds are SpinalMuscular Atrophy modulators. The invention further provides methods oftreating, preventing, or ameliorating Spinal Muscular Atrophy,comprising administering to a subject in need thereof an effectiveamount of an SMN modulator (e.g., a compound of the invention).

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

Within certain aspects, SMN modulators provided herein are compounds ofFormula X and salts thereof:

wherein A′ is phenyl which is substituted with 0, 1, 2, or 3substituents independently selected from C₁-C₄alkyl, wherein 2C₁-C₄alkyl groups can combine with the atoms to which they are bound toform a 5-6 membered ring and is substituted with 0 or 1 substituentsselected from oxo, oxime and, hydroxy, haloC₁-C₄alkyl, dihaloC₁-C₄alkyl,trihaloC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy-C₃-C₇cycloalkyl,haloC₁-C₄alkoxy, dihaloC₁-C₄alkoxy, trihaloC₁-C₄alkoxy, hydroxy, cyano,halogen, amino, mono- and di-C₁-C₄alkylamino, heteroaryl, C₁-C₄alkylsubstituted with hydroxy, C₁-C₄alkoxy substituted with aryl, amino,—C(O)NH C₁-C₄alkyl-heteroaryl, —NHC(O)—C₁-C₄alkyl-heteroaryl, C₁-C₄alkylC(O)NH— heteroaryl, C₁-C₄alkyl NHC(O)— heteroaryl, 3-7 memberedcycloalkyl, 5-7 membered cycloalkenyl or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms, independently, selected from S, O and N,wherein heteroaryl has 5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatomsselected from N, O and S and substituted with 0, 1, or 2 substituentsindependently selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH,trihaloC₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂,hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7memberheterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A′ is 6 member heteroaryl having 1-3ring nitrogen atoms, which 6 member heteroaryl is substituted by phenylor a heteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and substituted with 0, 1, or 2substituents independently selected from C₁-C₄alkyl, mono- anddi-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; or A′ isbicyclic heteroaryl having 9 to 10 ring atoms and 1, 2, or 3 ringheteroatoms independently selected from N, O or S, which bicyclicheteroaryl is substituted with 0, 1, or 2 substituents independentlyselected from oxo, cyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy and C₁-C₄alkoxy substituted with hydroxy,C₁-C₄alkoxy, amino and mono- and di-C₁-C₄alkylamino; B is a group of theformula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄akylamino; R₅ and R₆ areindependently selected from hydrogen and fluorine; or R and R₃, taken incombination form a fused 5 or 6 member heterocyclic ring having 0 or 1additional ring heteroatoms selected from N, O or S; R, and R₃, taken incombination form a C₁-C₃alkylene group; R, and R₅, taken in combinationform a C₁-C₃alkylene group; R₃ and R₄, taken in combination with thecarbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; Xis CR_(A′)R_(B′), NR₇ or a bond; R₇ is hydrogen, or C₁-C₄alkyl; R_(A′)and R_(B′) are independently selected from hydrogen and C₁-C₄alkyl, orR_(A′) and R_(B′), taken in combination, form a divalent C₂-C₅alkylenegroup; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or takenin combination with R₆ form a double bond; or B is a group of theformula:

wherein Y is C or O and when Y is O R₁₁ and R₁₂ are both absent; p and qare independently selected from the group consisting of 0, 1, and 2; R₉and R₁₃ are independently selected from hydrogen and C₁-C₄alkyl; R₁₀ andR₁₄ are independently selected from hydrogen, amino, mono- anddi-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionally substitutedwith hydroxy, amino or mono- and di-C₁-C₄akylamino; R₁₁ is hydrogen,C₁-C₄alkyl, amino or mono- and di-C₁-C₄akylamino; R₁₂ is hydrogen orC₁-C₄alkyl; or R₉ and R₁₁, taken in combination form a saturatedazacycle having 4 to 7 ring atoms which is optionally substituted with1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups.

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundaccording to the definition of Formula (X) or subformulae thereof andone or more pharmaceutically acceptable carriers.

In another embodiment, the invention provides a combination, inparticular a pharmaceutical combination, comprising a therapeuticallyeffective amount of the compound according to the definition of Formula(X) or subformulae thereof and one or more therapeutically active.

One embodiment of the invention is to provide a method for treating,preventing, or ameliorating an SMN-deficiency-related condition,comprising administering to a subject in need thereof an effectiveamount of an SMN modulator, or a pharmaceutical composition comprisingthe same.

Another embodiment of the invention is a method of modulating SMNprotein through the administration of an SMN modulator. In anotherembodiment, said SMN modulator is capable of increasing one or more ofFL-SMN or SMNΔ7 levels. In still another embodiment, said SMN modulatoris capable of preventing exon 7 from being spliced from the SMNtranscript.

The present invention is based on the discovery that the SMN modulatorsof the invention (e.g., compounds of formula (X) and/or subformulaethereof) are capable of modulating SMN proteins, e.g., through SMNpromoter activation, splicing modulation (e.g., preventing exon7 frombeing spliced out of the SMN gene), and/or SMN protein stabilitymodulation.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention provides compounds that modulateSMN activity. Such compounds may be used in vitro or in vivo to modulate(preferably increase) SMN production and activity in a variety ofcontexts.

In a first embodiment, the invention provides compounds of Formula X andpharmaceutically acceptable salts thereof, which modulate SMN activity.Compounds of Formula X are represented by the structure:

wherein A′ is phenyl which is substituted with 0, 1, 2, or 3substituents independently selected from C₁-C₄alkyl, wherein 2C₁-C₄alkyl groups can combine with the atoms to which they are bound toform a 5-6 membered ring and is substituted with 0 or 1 substituentsselected from oxo, oxime and, hydroxy, haloC₁-C₄alkyl, dihaloC₁-C₄alkyl,trihaloC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkoxy-C₃-C₇cycloalkyl,haloC₁-C₄alkoxy, dihaloC₁-C₄alkoxy, trihaloC₁-C₄alkoxy, hydroxy, cyano,halogen, amino, mono- and di-C₁-C₄alkylamino, heteroaryl, C₁-C₄alkylsubstituted with hydroxy, C₁-C₄alkoxy substituted with aryl, amino,—C(O)NH C₁-C₄alkyl-heteroaryl, —NHC(O)—C₁-C₄alkyl-heteroaryl, C₁-C₄alkylC(O)NH— heteroaryl, C₁-C₄alkyl NHC(O)— heteroaryl, 3-7 memberedcycloalkyl, 5-7 membered cycloalkenyl or 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms, independently, selected from S, O and N,wherein heteroaryl has 5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatomsselected from N, O and S and substituted with 0, 1, or 2 substituentsindependently selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH,trihaloC₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, —C(O)NH₂, —NH₂, —NO₂,hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7memberheterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A′ is 6 member heteroaryl having 1-3ring nitrogen atoms, which 6 member heteroaryl is substituted by phenylor a heteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S and substituted with 0, 1, or 2substituents independently selected from C₁-C₄alkyl, mono- anddi-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl and mono- and di-C₁-C₄alkylaminoC₁-C₄alkyl; or A′ isbicyclic heteroaryl having 9 to 10 ring atoms and 1, 2, or 3 ringheteroatoms independently selected from N, O or S, which bicyclicheteroaryl is substituted with 0, 1, or 2 substituents independentlyselected from oxo, cyano, halogen, hydroxy, C₁-C₄alkyl, C₂-C₄alkenyl,C₂-C₄alkynyl, C₁-C₄alkoxy and C₁-C₄alkoxy substituted with hydroxy,C₁-C₄alkoxy, amino and mono- and di-C₁-C₄alkylamino; B is a group of theformula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄akylamino; R₅ and R₆ areindependently selected from hydrogen and fluorine; or R and R₃, taken incombination form a fused 5 or 6 member heterocyclic ring having 0 or 1additional ring heteroatoms selected from N, O or S; R, and R₃, taken incombination form a C₁-C₃alkylene group; R, and R₅, taken in combinationform a C₁-C₃alkylene group; R₃ and R₄, taken in combination with thecarbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; Xis CR_(A′)R_(B′), NR₇ or a bond; R₇ is hydrogen, or C₁-C₄alkyl; R_(A′)and R_(B′) are independently selected from hydrogen and C₁-C₄alkyl, orR_(A′) and R_(B′), taken in combination, form a divalent C₂-C₅alkylenegroup; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or takenin combination with R₆ form a double bond; or B is a group of theformula:

wherein Y is C or O and when Y is O R₁₁ and R₁₂ are both absent; p and qare independently selected from the group consisting of 0, 1, and 2; R₉and R₁₃ are independently selected from hydrogen and C₁-C₄alkyl; R₁₀ andR₁₄ are independently selected from hydrogen, amino, mono- anddi-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionally substitutedwith hydroxy, amino or mono- and di-C₁-C₄akylamino; R₁₁ is hydrogen,C₁-C₄alkyl, amino or mono- and di-C₁-C₄akylamino; R₁₂ is hydrogen orC₁-C₄alkyl; or R₉ and R₁₁, taken in combination form a saturatedazacycle having 4 to 7 ring atoms which is optionally substituted with1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups.

In a second embodiment, the invention a compound, or salt thereof,according to the first embodiment wherein A′ is selected from:

In a third embodiment, the invention is a compound, or salt thereof,according any one of the first or second embodiments, which compound isrepresented by Formula (I)

Wherein Y is N or C—R^(a); R^(a) is hydrogen or C₁-C₄alkyl; R^(b) ishydrogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, cyano, halogen, trihaloC₁-C₄alkyl or trihalo C₁-C₄alkoxy; R^(c) and R^(d) are each,independently, hydrogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, trihaloC₁-C₄alkyl, trihalo C₁-C₄alkoxy or heteroaryl; A is 6 member heteroarylhaving 1-3 ring nitrogen atoms, which 6 member heteroaryl is substitutedwith 0, 1, or 2 substituents independently selected from oxo,C₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A is 5 member heteroaryl having 1-3ring heteroatoms independently selected from N, O and S and substitutedwith 0, 1, or 2 substituents independently selected from C₁-C₄alkyl,hydroxyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A and R^(c), together with the atoms towhich they are bound, form a 6 member aryl with 0, 1, or 2 substituentsindependently selected from cyano, halogen, hydroxy, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy and C₁-C₄alkoxy substituted withhydroxy, C₁-C₄alkoxy, amino and mono- and di-C₁-C₄alkylamino; B is agroup of the formula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄akylamino; R₅ and R₆ areindependently selected from hydrogen and fluorine; or R and R₃, taken incombination form a fused 5 or 6 member heterocyclic ring having 0 or 1additional ring heteroatoms selected from N, O or S; R, and R₃, taken incombination form a C₁-C₃alkylene group; R, and R₅, taken in combinationform a C₁-C₃alkylene group; R₃ and R₄, taken in combination with thecarbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; Xis CR_(A′)R_(B′), NR₇ or a bond; R₇ is hydrogen, or C₁-C₄alkyl; R_(A′)and R_(B′) are independently selected from hydrogen and C₁-C₄alkyl, orR_(A′) and R_(B′), taken in combination, form a divalent C₂-C₅alkylenegroup; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or takenin combination with R₆ form a double bond; or B is a group of theformula:

wherein p and q are independently selected from the group consisting of0, 1, and 2; R₉ and R₁₃ are independently selected from hydrogen andC₁-C₄alkyl; R₁₀ and R₁₄ are independently selected from hydrogen, amino,mono- and di-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionallysubstituted with hydroxy, amino or mono- and di-C₁-C₄akylamino; R₁₁ ishydrogen, C₁-C₄alkyl, amino or mono- and di-C₁-C₄akylamino; R₁₂ ishydrogen or C₁-C₄alkyl; or R₉ and R₁₁, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken incombination form a saturated azacycle having 4 to 7 ring atoms which isoptionally substituted with 1-3 C₁-C₄alkyl groups.

In a fourth embodiment, the invention is a compound, or a salt thereof,according to the third embodiment, wherein A is 6 member heteroarylhaving 1-3 ring nitrogen atoms, which 6 member heteroaryl is substitutedwith 0, 1, or 2 substituents independently selected from oxo,C₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl.

In a fifth embodiment, the invention is a compound, or a salt thereof,according to any one of the third or fourth embodiments, wherein A isselected from:

In a sixth embodiment, the invention is a compound, or a salt thereof,according to the third embodiment, wherein A is 5 member heteroarylhaving 1-3 ring heteroatoms independently selected from N, O and S andsubstituted with 0, 1, or 2 substituents independently selected fromC₁-C₄alkyl, hydroxyl, mono- and di-C₁-C₄alkylamino,hydroxyC₁-C₄alkylamino, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl.

In a seventh embodiment, the invention is a compound, or a salt thereof,according to any one of the third or sixth embodiments, wherein A isselected from:

In an eighth embodiment, the invention is a compound, or salt thereof,according to any one of the first through seventh embodiments, wherein Bis a group of the formula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄akylamino; R₅ and R₆ are hydrogen;or R and R₃, taken in combination form a fused 5 or 6 memberheterocyclic ring having 0 or 1 additional ring heteroatoms selectedfrom N, O or S; R, and R₃, taken in combination form a C₁-C₃alkylenegroup; R, and R₅, taken in combination form a C₁-C₃alkylene group; R₃and R₄, taken in combination with the carbon atom to which they attach,form a spirocyclicC₃-C₆cycloalkyl; X is CR_(A′)R_(B′), 0, NR₇ or a bond;R_(A′) and R_(B′) are independently selected from hydrogen andC₁-C₄alkyl, or R_(A′) and R_(B′), taken in combination, form a divalentC₂-C₅alkylene group; Z is CR₈ or N; when Z is N, X is a bond; R₈ ishydrogen or taken in combination with R₆ form a double bond.

In a ninth embodiment, the invention is a compound, or salt thereof,according to any one of the first through seventh embodiments, wherein Bis a group of the formula:

wherein p and q are independently selected from the group consisting of0, 1, and 2; R₉ and R₁₃ are independently selected from hydrogen andC₁-C₄alkyl; R₁₀ and R₁₄ are independently selected from hydrogen, amino,mono- and di-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionallysubstituted with hydroxy, amino or mono- and di-C₁-C₄akylamino; R₁₁ ishydrogen, C₁-C₄alkyl, amino or mono- and di-C₁-C₄akylamino; R₁₂ ishydrogen or C₁-C₄alkyl; or R₉ and R₁₁, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken incombination form a saturated azacycle having 4 to 7 ring atoms which isoptionally substituted with 1-3 C₁-C₄alkyl groups.

In a tenth embodiment, the invention is a compound, or a salt thereof,according to any one of the first through ninth embodiments, whichcompound is represented by Formula (XX):

wherein R^(b) is hydrogen or hydroxy; R^(c) is hydrogen or halogen; andR^(d) is halogen.

In an eleventh embodiment, the invention is a compound, or salt thereofaccording to any one of the first through ninth embodiments, whichcompound is represented by Formula (II):

wherein R^(b) is hydroxyl, methoxy, trifluoromethyl or trifluoromethoxy.

In a twelfth embodiment, the invention is a compound, or salt thereof,according to any one of the first through ninth embodiments, whichcompound is represented by Formula (III):

wherein R^(b) is hydroxyl, methoxy, trifluoromethyl or trifluoromethoxy;and R^(e) is hydrogen, hydroxy or methoxy.

In a thirteenth embodiment, the invention is a compound, or saltthereof, according to any one of the third through ninth or elevenththrough twelfth embodiments, wherein Y is N.

In a fourteenth embodiment, the invention is a compound, or saltthereof, according to any one of the third through ninth or elevenththrough twelfth embodiments, wherein Y is CH.

In a fifteenth embodiment, the invention is a compound, or salt thereof,according of any one of the first through eighth or tenth throughfourteenth embodiments, wherein B is selected from

wherein Z is NH or N(Me).

In a sixteenth embodiment, the invention is a compound, or salt thereof,according of any one of the first through eighth or tenth throughfifteenth embodiments, wherein B is

In a seventeenth embodiment compound, or salt thereof, according of anyone of the first through seventh or ninth through fourteenthembodiments, wherein B is selected from

In an eighteenth embodiment, the invention is a compound, or saltthereof, according of any one of the first through seventh, ninththrough fourteenth or seventeenth embodiments wherein B is

In a nineteenth embodiment, the invention is a compound or salt thereofselected from the group consisting of:

-   5-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   6-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen-2-ol;-   5-(2-Methoxyquinolin-3-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(3-Methoxynaphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-Methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   4-(3-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)-one;-   5-(3-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)pyridin-2-ol;-   5-(3-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)-one;-   N-Methyl-5-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   1-Methyl-4-(4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-3-(trifluoromethoxy)phenyl)pyridin-2(1H)-one;-   5-(4-(3,5-Dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol;-   5-(3-Hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)-one;-   4-(3-Hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)-one;-   5-(3-Hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)pyridin-2-ol;-   3-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalene-2,7-diol;-   3-(5-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2-yl)naphthalene-2,7-diol;-   3-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen-2-ol.hydrobromide    salt;-   3-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2-ol;-   2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-4-(1H-pyrazol-1-yl)phenol;-   5-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   3-Chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   3-Methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(5-methyloxazol-2-yl)phenol;-   2-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4-thiadiazole-   2-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol;-   5-(7-Methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   6-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-7-ol;-   3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)benzonitrile;-   3-fluoro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)benzonitrile;-   methyl    3-fluoro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)benzoate;-   5-(2-methoxy-4-(3-(methylamino)-1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   7-methoxy-6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinoline-2-carbonitrile;-   4-(3-methoxy-4-(5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)-one;-   4-(3-chloro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)-one;-   5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-chloro-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   N-methyl-5-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine    Hydrochloride salt;-   2-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-1,3,4-thiadiazole;-   5-(2-chloro-4-(6-methoxypyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(4-(6-aminopyridin-3-yl)-2-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-fluoro-4-(3-methyl-1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-fluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2,3-difluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2,5-difluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   2-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-((3a    R,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole;-   5-(2-chloro-5-fluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(3-fluoro-5-(1H-pyrazol-4-yl)pyridin-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(4-(2-aminopyrimidin-4-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(5-(2-aminopyrimidin-4-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(4-(2,4-dimethylthiazol-5-yl)-2,5-difluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(4-(2,4-dimethylthiazol-5-yl)-2,3-difluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   4-(3-hydroxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one;-   5-(2-fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   2-(2-fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole;-   5-(2,3-difluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   6-methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinolin-1(2H)-one;-   5-(2-chloro-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-chloro-4-(1H-1,2,3-triazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-chloro-4-(2H-1,2,3-triazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-chloro-4-(1H-1,2,4-triazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(4-(3-amino-1H-pyrazol-1-yl)-2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   2-(2-chloro-4-(1H-imidazol-1-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole;-   5-(2-chloro-4-(1H-imidazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-fluoro-4-(1H-imidazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-methoxy-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(4-(2,4-dimethylthiazol-5-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-methoxy-4-(pyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-methoxy-4-(2-methoxypyridin-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2-methoxy-4-(6-methoxypyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   2-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((3a    R,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole;-   2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole;-   2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1,3,4-thiadiazole;-   1-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)morpholin-2-yl)-N,    N-dimethylmethanamine;-   2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2-methyl-2,7-diazaspiro[4.5]decan-7-yl)-1,3,4-thiadiazole;-   2-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole;-   2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole;-   2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole;-   2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol;-   5-(3-chloro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)pyridin-2(1H)-one;-   2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(3-(methylamino)-1H-pyrazol-1-yl)phenol;-   3-fluoro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   3,4-difluoro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   6-hydroxy-5-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-one;-   2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol;-   3-fluoro-2-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol    Di-hydrochloride salt;-   3-chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole;-   2-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole;-   2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-3-fluoro-5-(1H-pyrazol-4-yl)phenol;-   4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one;-   4-hydroxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one;-   3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one;-   1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one;-   2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole    Hydrochloride Salt;-   2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[4.5]decan-2-yl)-1,3,4-thiadiazole    Hydrochloride Salt;-   (R)-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazin-2-yl)methanol    Hydrochloride Salt;-   2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)benzo[b]thiophene-5-carbonitrile;    and-   5-(3-chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine.

In another embodiment, the invention is a compound or salt thereofselected from the group consisting of:

-   5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   5-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;-   3-fluoro-2-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   3-fluoro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol;-   5-(2-chloro-5-fluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine;    and-   Synthesis of    4-hydroxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one.

In a twentieth embodiment, the invention is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound according toany one of the first through nineteenth embodiments, or apharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable carriers.

In a twentyfirst embodiment, the invention is a combination comprising atherapeutically effective amount of a compound according to any one ofthe first through nineteenth embodiments or a pharmaceuticallyacceptable salt thereof and one or more therapeutically activeco-agents.

In a twentysecond embodiment, the invention is a method to treat,prevent or ameliorate an SMN-deficiency-related condition, comprisingadministering to a subject in need thereof an effective amount of acompound or salt thereof of any one of the first through nineteenthembodiments.

In a twentythird embodiment, the invention is the method of thetwentysecond embodiment, wherein said SMN-deficiency-related conditionis Spinal Muscular Atrophy.

In a twentyfourth embodiment, the invention is a compound according toany one of claims the first through nineteenth embodiments or apharmaceutically acceptable salt thereof, for use as a medicament.

In a twentyfifth embodiment, the invention is a compound according toany one of the first through nineteenth embodiments or apharmaceutically acceptable salt thereof, for use in the treatment of anSMN-deficiency-related condition.

In a twentysixth embodiment, the invention is the compound according tothe twentyfifth embodiment, or pharmaceutically acceptable salt thereof,for use in the treatment of spinal muscular atrophy.

In a twentyseventh embodiment, the invention is the use of a compoundaccording to any one of the first through nineteenth embodiments or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the treatment of spinal muscular atrophy.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “SMN modulator” includes agents, such as thecompounds of the invention, which possess the ability to modulate, e.g.,increase, SMN protein levels by at least one of multiple possiblemechanisms. A non-limiting set of mechanisms includes SMN promoteractivation, splicing modulation (e.g., preventing exon7 from beingspliced out of the SMN gene), and SMN protein stability modulation. SMNmodulators can modulate, e.g., increase FL-SMN and/or SMNΔ7 levels viaany of said mechanisms, and/or can prevent SMNΔ7 from being degraded.

As used herein, the term “compounds of the invention” include but arenot limited to the compounds of formula (X).

As used herein, the term “SMN-deficiency-related conditions” includesbut is not limited to Spinal Muscular Atrophy (SMA), neurogenic-typearthrogryposis multiplex congenita (congenital AMC), and amyotrophiclateral sclerosis (ALS).

As used herein, the term “Spinal Muscular Atrophy”, “SMA,” include threeforms of childhood-onset SMA: Type I (Werdnig-Hoffmann disease); Type II(intermediate, chronic form), Type III (Kugelberg-Welander disease, orJuvenile Spinal Muscular Atrophy); Adult-onset type IV; as well as otherforms of SMA, including X-linked disease, Spinal Muscular Atrophy withrespiratory distress (SMARD), spinal and bulbar muscular atrophy(Kennedy's disease, or Bulbo-Spinal Muscular Atrophy), and distal spinalmuscular atrophy.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “C₁₋₁₀alkyl” refers to a fully saturatedbranched or unbranched hydrocarbon moiety having 1 to 10 carbon atoms.The terms “C₁₋₆alkyl” and “C₁₋₄alkyl” are to be construed accordingly.Representative examples of C₁₋₆alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl andn-decyl.

As used herein, the term “C₁₋₁₀alkylene” refers to divalent alkyl groupas defined herein above having 1 to 10 carbon atoms. The terms“C₁₋₆alkylene” and “C₁₋₄alkylene” are to be construed accordingly.Representative examples of C₁₋₁₀alkylene include, but are not limitedto, methylene, ethylene, n-propylene, iso-propylene, n-butylene,sec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene,neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene,2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene andn-decylene.

As used herein, the term “haloC₁₋₄alkyl” refers to a C₁₋₄alkyl group asdefined herein, wherein at least one of the hydrogen atoms is replacedby a halo atom. The haloC₁₋₄alkyl group can be monohaloC₁₋₄alkyl,dihaloC₁₋₄alkyl or polyhaloC₁₋₄alkyl including perhaloC₁₋₄alkyl. AmonohaloC₁₋₄alkyl can have one iodo, bromo, chloro or fluoro within thealkyl group. DihaloC₁₋₄alkyl and polyhaloC₁₋₄alkyl groups can have twoor more of the same halo atoms or a combination of different halo groupswithin the alkyl. Typically the polyhaloC₁₋₄alkyl group contains up to12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Non-limitingexamples of haloC₁₋₄alkyl include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. A perhaloC₁₋₄alkyl group refers to an C₁₋₄alkyl grouphaving all hydrogen atoms replaced with halo atoms.

The term “aryl” refers to an aromatic hydrocarbon group having 6-20carbon atoms in the ring portion. Typically, aryl is monocyclic,bicyclic or tricyclic aryl having 6-20 carbon atoms and includes one ormore aromatic rings fused to one or more non-aromatic hydrocarbon rings.Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.

As used herein, the term “C₁₋₁₀alkoxy” refers to C₁₋₁₀alkyl-O—, whereinC₁₋₁₀alkyl is defined herein above. The term “C₁₋₄alkoxy” refers toC₁₋₄alkyl-O—, wherein C₁₋₄alkyl is defined herein above. Representativeexamples of C₁₋₁₀alkoxy include, but are not limited to, methoxy,ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy,heptyloxy, octyloxy- and decyloxy-.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to asaturated or unsaturated non-aromatic ring or ring system, which is a4-, 5-, 6-, or 7-membered monocyclic ring containing 1, 2 or 3heteroatoms selected from O, S and N, a 7-, 8-, 9-, 10-, 11-, or12-membered bicyclic ring system containing 1, 2, 3, 4 or 5 heteroatomsselected from O, S and N, or a 10-, 11-, 12-, 13-, 14- or 15-memberedtricyclic ring system and containing 1, 2, 3, 4, 5, 6 or 7 heteroatomsselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached via a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings. Examples ofheterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane and thiomorpholine.

As used herein, the term “C₃₋₁₂cycloalkyl” refers to saturated orunsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12carbon atoms. The term “C₃₋₁₈cycloalkyl” refers to a fully saturated orunsaturated monocyclic hydrocarbon group of 3-8 carbon atoms. The term“C₃₋₇cycloalkyl” refers to saturated or unsaturated monocyclic, bicyclicor tricyclic hydrocarbon groups of 3-7 carbon atoms. Exemplarymonocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl. Exemplary bicyclic hydrocarbon groups include bornyl,indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl. Exemplary tricyclic hydrocarbon groups include, forexample, adamantyl.

As used herein the term “C₃₋₁₂cycloalklyoxy” refers toC₃₋₁₂cycloalkyl-O—, wherein C₃₋₁₂cycloalkyl is defined herein above.Representative examples of C₃₋₁₂cycloalklyoxy include, but are notlimited to monocyclic groups such as cyclopropoxy, cyclobutoxy,cyclopentyloxy, cyclopentenyloxy, cyclohexyloxy and cyclohexenyloxy andthe like. Exemplary bicyclic hydrocarbon groups include bornyloxy,indyloxy, hexahydroindyloxy, tetrahydronaphthyloxy,decahydronaphthyloxy, bicyclo[2.1.1]hexyloxy, bicyclo[2.2.1]heptyloxy,bicyclo[2.2.1]heptenyloxy, 6,6-dimethylbicyclo[3.1.1]heptyloxy,2,6,6-trimethylbicyclo[3.1.1]heptyloxy, bicyclo[2.2.2]octyloxy and thelike. Exemplary tricyclic hydrocarbon groups include, for example,adamantyloxy.

As used herein, the term “aryloxy” refers to both an —O-aryl and an—O-heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term “heteroaryl” refers to a 5-, 6-, or 7-memberedmonocyclic aromatic ring containing 1, 2, 3 or 4 heteroatoms selectedfrom O, S and N, an 8-, 9-, or 10-membered fused bicyclic ring systemcontaining 1, 2, 3, 4 or 5 heteroatoms selected from O, S and N, or an11-, 12-, 13-, or 14-membered fused tricyclic ring system containing 1,2, 3, 4, 5 or 6 heteroatoms selected from O, S and N, wherein at leastone of the rings of the bicyclic or tricyclic ring systems is fullyaromatic. Typical heteroaryl groups include 2- or 3-thienyl, 2- or3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-,or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl, 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-,6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-,6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-,6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 1-, 4-, 5-, 6-, 7-, or8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-,or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-,3-, 4-, 5-, 6-, 7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-,2-, 3-, 4-, 5-,6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-,or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-,2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-,or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-,or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl, 2-, 3-, 4-, 5-, 6-, 7-, or8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-,5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-,5-, 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-,4-, 5-, 6-, or 7-benzothiazolyl.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereoisomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts.” The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C, are present. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the Formula (X). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labeled compounds of Formula (X) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of Formula (X) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of Formula (X) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof Formula (X) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of Formula (X).

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviate, inhibit,prevent and/or ameliorate a condition, or a disorder or a disease (i)mediated by Survival of Motor Neuron (SMN) gene or gene product, or bySMNΔ7 degradation, or by the relative levels of FL-SMN and SMNΔ7 (ii)associated with SMN activity, or (iii) characterized by activity (normalor abnormal) of SMN; or (2) reducing or inhibiting the activity of SMN;or (3) reducing or inhibiting the expression of SMN1 or SMN2.

In another non-limiting embodiment, the term “a therapeuticallyeffective amount” refers to the amount of the compound of the presentinvention that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reducing or inhibiting the activity of SMN; or at leastpartially reducing or inhibiting the expression of SMN, in both cases bymodulating the relative levels of FL-SMN and SMNΔ7.

The phrases “therapeutically effective amount” and “effective amount”are used herein to mean an amount sufficient to reduce by at least about15 percent, preferably by at least 50 percent, more preferably by atleast 90 percent, and most preferably prevent, a clinically significantdeficit in the activity, function and response of the host.Alternatively, a therapeutically effective amount is sufficient to causean improvement in a clinically significant condition/symptom in thehost.

The effective amount can vary depending on such factors as the size andweight of the subject, the type of illness, or the particular compoundof the invention. For example, the choice of the compound of theinvention can affect what constitutes an “effective amount.” One ofordinary skill in the art would be able to study the factors containedherein and make the determination regarding the effective amount of thecompounds of the invention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of an SMN-deficiency-relatedcondition. Further, several divided dosages, as well as staggereddosages, can be administered daily or sequentially, or the dose can becontinuously infused, or can be a bolus injection. Further, the dosagesof the compound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat,” “treating,” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically (e.g., throughstabilization of a discernible symptom), physiologically, (e.g., throughstabilization of a physical parameter), or both. In yet anotherembodiment, “treat,” “treating,” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. The pharmaceutical composition can be formulated forparticular routes of administration such as oral administration,parenteral administration, and rectal administration, etc. In addition,the pharmaceutical compositions of the present invention can be made upin a solid form (including without limitation capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (includingwithout limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

lubricants, e.g., silica, talcum, stearic acid, its magnesium or calciumsalt and/or polyethyleneglycol; for tablets also

binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired

disintegrants, e.g., starches, agar, alginic acid or its sodium salt, oreffervescent mixtures; and/or

absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems, will in particular, be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of Formula I in free form or in salt form, exhibitvaluable pharmacological properties, e.g. full length SMN proteinproduction modulating properties, e.g. as indicated in in vitro and invivo tests as provided in the next sections, and are therefore indicatedfor therapy or for use as research chemicals, e.g. as tool compounds.

Thus, as a further embodiment, the present invention provides the use ofa compound of Formula (X) or a salt thereof in therapy. In a furtherembodiment, the therapy is selected from a disease which may be treatedby modulating full length SMN protein production. In another embodiment,the disease is selected from the afore-mentioned list, suitably SpinalMuscular Atrophy.

In another embodiment, the invention provides a method of treating adisease which is treated by modulating full length SMN proteinproduction comprising administration of a therapeutically acceptableamount of a compound of Formula (X) or salt thereof to a patient in needof such therapy. In a further embodiment, the disease is selected fromthe afore-mentioned list, suitably Spinal Muscular Atrophy.

Thus, as a further embodiment, the present invention provides the use ofa compound of Formula (X) or salt thereof for the manufacture of amedicament. In a further embodiment, the medicament is for treatment ofa disease which may be treated by modulation of SMN protein production.In another embodiment, the disease is selected from the afore-mentionedlist, suitably Spinal Muscular Atrophy.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound of Formula (X) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a SpinalMuscular Atrophy. Products provided as a combined preparation include acomposition comprising the compound of Formula (X) and the othertherapeutic agent(s) together in the same pharmaceutical composition, orthe compound of Formula (X) and the other therapeutic agent(s) inseparate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of Formula (X) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable carrier, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of Formula (X). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

Preparations of Compounds

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, phenol, amino and carboxylic acid.Suitable protecting groups for hydroxy or phenol include trialkylsilylor diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl,and the like. Suitable protecting groups for amino, amidino andguanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.Suitable protecting groups for carboxylic acid include alkyl, aryl orarylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein. The use of protecting groups is described in detail inGreen, T. W. and P. G. M. Wutz, Protective Groups in Organic Synthesis(1999), 3rd Ed., Wiley. The protecting group may also be a polymerresin, such as a Wang resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a subjectand thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

The following reaction schemes illustrate methods to make compounds ofthis invention. It is understood that one skilled in the art would beable to make these compounds by similar methods or by methods known toone skilled in the art. In general, starting components and reagents maybe obtained from sources such as Sigma Aldrich, Lancaster Synthesis,Inc., Maybridge, Matrix Scientific, TCl, and Fluorochem USA, Strem,other commercial vendors, or synthesized according to sources known tothose skilled in the art, or prepared as described in this invention. A,B, X, R, R¹, R², R³, R⁴, are defined as in the Specification unlessspecifically defined.

In general, thiadiazole compounds of Formula (X) of this invention canbe synthesized following the general procedure described in Scheme 1.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction Scheme 1 as follows:

Di-halothiadiazole (1) reacts in a displacement reaction or ametal-mediated cross coupling reaction (Buchwald) with an alcohol or anamine (B) to provide thiadiazole intermediate (2). Transitionmetal-mediated cross coupling reaction, such as a Suzuki reaction,between halide compound (2) and a substituted aryl or heteroarylcompound A, such as a boronate acid or boronate ester, provides compound(3) of Formula (X) of the invention.

In an alternative manner, compounds of Formula (X) can be synthesizedfollowing the general procedure described in Scheme 2.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction Scheme 2 as follows:

Di-halothiadiazole (1) reacts in a transition metal-mediated crosscoupling reaction, such as a Suzuki reaction, with a boronate acid orester, to provide thiadiazole intermediate (2). Thiadiazole intermediate(2) reacts via second metal-mediated cross coupling, such as a Suzukireaction, to provide thiadiazole (3) of Formula (X) of the invention.

Compounds of Formula (X) can also be prepared following the generalprocedure described in Scheme 3.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe invention are prepared in the above reaction Scheme 3 as follows:

Substituted aryl or heteroaryl carboxylic acid (4) reacts withhydrazinecarbothioamide and phosphoryl chloride to form aminothiadiazole intermediate (5). Thiadiazole intermediate (5) is thenreacted with tert-butylnitrile and CuBr₂ to provide thiadiazoleintermediate (6). Thiadiazole intermediate (6) reacts in a displacementreaction or a metal-mediated cross coupling reaction (Buchwald) with analcohol or an amine (B) to provide thiadiazole (3) of Formula (X) of theinvention.

General Schemes 1, 2 and 3 can be followed for a variety of aromatic Agroups such as substituted phenols, naphthyls, heteroaryls, and thelike, and for a variety of amine B groups such as substitutedaminopiperidines, piperidines, piperazines, homopiperazines,pyrrolidines, bicyclic amines, and the like, to provide compounds ofFormula (X) of the invention. Routine protecting group strategies may berequired to achieve final compounds of Formula (X).

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, catalysts and scavengers utilized tosynthesize the compounds of the present invention are eithercommercially available or can be produced by organic synthesis methodsknown to one of ordinary skill in the art. Further, the compounds of thepresent invention can be produced by organic synthesis methods known toone of ordinary skill in the art as shown in the following examples.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., LCMS, NMR,CHN. Abbreviations used are those conventional in the art, a list ofwhich is provided at the end of the experimental section.

Synthesis of Intermediates Intermediate 1: Synthesis of1-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole

Step 1: (4-Bromo-3-methoxyphenyl)hydrazine

4-Bromo-3-methoxyaniline (3.0 g, 14.85 mmol) was suspended inconcentrated HCl (50 mL) and the mixture was cooled to 0° C. in theice-water bath. A solution of sodium nitrite (1.23 g, 17.82 mmol) in 10mL water was added very slowly to the reaction mixture. The mixtureturned yellow, then brown with a yellow haze indicating diazotization.The diazonium salt was held at 0° C. for an hour and then a solution oftin(II) chloride dihydrate (10.05 g, 44.5 mmol) in concentrated HCl (20mL) was added very slowly (caution, extremely exothermic). The reactionwas stirred for 2 h at 0° C. then at RT overnight. The reaction wasfiltered and the filter cake was washed with cold H₂O to afford(4-bromo-3-methoxyphenyl)hydrazine as a tan solid (3.1 g, MS: 218[M+H⁺]).

Step 2: 1-(4-Bromo-3-methoxyphenyl)-1H-pyrazole

To a solution of (4-bromo-3-methoxyphenyl)hydrazine (62 g, 245 mmol) inethanol (310 mL) was added tetramethoxypropane (40.2 g, 245 mmol) over afew minutes, and the mixture was heated to an internal temperature of70° C. The mixture was stirred at 70° C. for 1.5 h then slowly cooled toRT. Ethanol was removed in vacuo and the residue was slurried in EtOAc.The residue was neutralized with 1M aqueous sodium hydroxide (˜700 mL)to cause precipitation. The biphasic mixture was filtered and thefiltrate was extracted with EtOAc, dried over sodium sulfate andconcentrated to provide 30 g of 1-(4-bromo-3-methoxyphenyl)-1H-pyrazoleas a black solid (30 g, MS: 254 [M+H⁺].).

Step 3:1-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole

1-(4-Bromo-3-methoxyphenyl)-1H-pyrazole (28.5 g, 113 mmol),bis(pinacolato)diboron (42.9 g, 169 mmol), potassium carbonate (15.56 g,113 mmol), and PdCl₂(dppf).CH₂Cl₂ adduct (9.20 g, 11.26 mmol) were addedto a 2 L round bottom flask, followed by addition of dioxane (700 mL).The reaction mixture was purged by N₂ and stirred under N₂ at aninternal temperature of 84° C. overnight. The reaction mixture wasfiltered through a disposable filter funnel and concentrated onto silicagel. The mixture was purified using column chromatography (20% EtOAc inheptanes). The desired fractions were collected and concentrated toprovide 13.5 g of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole.

Intermediate 2: Synthesis of(2-(Benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid

Step 1: Methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate

To a mixture of methyl 4-bromo-3,5-dihydroxybenzoate (18.8 g, 76 mmol)and potassium carbonate (5.26 g, 38.1 mmol) in DMF (190 mL) was addedbenzyl bromide (3.17 mL, 26.6 mmol). The mixture was stirred overnight,diluted with 200 mL water and acidified to pH 1 by slow addition ofconcentrated hydrochloric acid. The solution was extracted with 1:1ethyl acetate/ether (6×) and the combined extracts were washed withwater (8×), saturated sodium bicarbonate, brine, then dried overmagnesium sulfate and concentrated to provide an orange solid. The solidwas suspended in DCM (200 mL) and stirred overnight. The solid(primarily unreacted 4-bromo-3,5-dihydroxybenzoate) was removed byfiltration and the filtrate was concentrated to provide an orange oilwhich was purified by column chromatography (80 g silica gel, 2:1 DCM inheptane elution, followed by DCM elution) to provide methyl3-(benzyloxy)-4-bromo-5-hydroxybenzoate (4.66 g). MS (M+1)=337.0. ¹H NMR(400 MHz, CHLOROFORM-d) δ ppm 7.32-7.57 (m, 6H), 7.26 (d, J=1.52 Hz,1H), 5.77 (s, 1H), 5.22 (s, 2H), 3.93 (s, 3H) as well as thedi-benzylated methyl 3,5-bis(benzyloxy)-4-bromobenzoate (1.8 g).

Step 2: Methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate

To a mixture of methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (3.69 g,10.94 mmol) and potassium carbonate (3.03 g, 21.98 mmol) in DMF (27 mL)was added methyl iodide (0.753 mL, 12.04 mmol). The mixture was stirredovernight after which time it was diluted with water and extracted withethyl acetate (4×). The combined extracts were washed with water (8×),brine, dried over magnesium sulfate and concentrated to provide methyl3-(benzyloxy)-4-bromo-5-methoxybenzoate as a white solid (3.72 g). MS(M+1)=351.1; ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.59 (m, 7H),5.24 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H).

Step 3: 3-(Benzyloxy)-4-bromo-5-methoxybenzoic acid

To a solution of methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate (3.72 g,10.59 mmol) in 1:1 MeOH/THF (50 mL) was added aqueous sodium hydroxide(1 M, 53.0 mL, 53.0 mmol). After minutes the volatiles were removedunder reduced pressure and the solution acidified to pH 1 by addition ofconcentrated hydrochloric acid resulting in formation of a thick whiteprecipitate. The mixture was extracted with ethyl acetate (2×), and DCM(3×). The combined extracts were washed with brine, dried over magnesiumsulfate and concentrated to provide3-(benzyloxy)-4-bromo-5-methoxybenzoic acid as a white solid (3.41 g).MS (M−1)=335.0. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21-7.49 (m, 7H),5.16 (s, 2H), 3.91 (s, 3H).

Step 4: 3-(Benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide

To a suspension of 3-(benzyloxy)-4-bromo-5-methoxybenzoic acid (2.0 g,5.93 mmol) and 4 drops of DMF in DCM (40 mL) was slowly added oxalylchloride (0.57 mL, 6.52 mmol). After three hours the solvent was removedand the residue was redissolved in DCM (10 mL). To this solution wasslowly added a mixture of propargylamine (0.46 mL, 7.12 mmol) andtriethylamine (2.5 mL, 17.8 mmol) in DCM (2 mL). After 30 minutes thesolution was diluted with ether, washed with water (2×), 1 Mhydrochloric acid (2×), water, saturated sodium bicarbonate, brine, thendried over magnesium sulfate and concentrated to a yellow solid. Thesolid was triturated with diethyl ether and dried under vacuum toprovide 3-(benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide(1.88 g) as an off-white solid. MS=374.0 (M+1).

Step 5: 2-(3-(Benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole

To a solution of3-(benzyloxy)-4-bromo-5-methoxy-N-(prop-2-yn-1-yl)benzamide (0.455 g,1.22 mmol) in dioxane (12 mL) was added sodium hydride (60% wt, 0.146 g,3.65 mmol) and the mixture was heated at reflux for six hours. Themixture was cooled to room temperature, quenched by slow addition ofwater, and diluted with ethyl acetate. The mixture was washed withwater, saturated sodium bicarbonate, brine, then dried over magnesiumsulfate and concentrated. Flash column chromatography (12 g silica, 2%ethyl acetate in DCM) provided2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (198 mg) as anoff-white solid. MS=374 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.55(d, J=7.58 Hz, 2H), 7.43 (t, J=7.33 Hz, 2H), 7.32-7.39 (m, 2H), 7.27 (d,J=2.02 Hz, 1H), 6.89 (d, J=1.01 Hz, 1H), 5.27 (s, 2H), 4.02 (s, 3H),2.44 (d, J=1.52 Hz, 3H).

Step 6: (2-(Benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronicacid

To a stirred solution of2-(3-(benzyloxy)-4-bromo-5-methoxyphenyl)-5-methyloxazole (197 mg, 0.526mmol) in THF (1.3 mL) cooled to −78° C. was added n-butyl lithium (2.5 Min hexanes, 232 uL, 0.579 mmol). The solution was stirred for 15 minutesafter which time trimethyl borate (235 uL, 2.11 mmol) was added and thesolution was allowed to slowly warm to room temperature overnight. Thereaction was quenched by addition of 0.1 M HCl and was diluted withethyl acetate, washed with water, brine, dried over magnesium sulfateand concentrated. Flash column chromatography (12 g silica, 0-100% ethylacetate in DCM over 30 column volumes) provided(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid (63mg) as a white foam. MS=340.1 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δppm 7.28-7.46 (m, 5H), 7.25 (d, J=1.01 Hz, 1H), 7.08 (br. s, 1H), 6.85(d, J=1.01 Hz, 1H), 5.17 (s, 2H), 3.95 (s, 3H), 2.38 (d, J=1.52 Hz, 3H).

Intermediate 3: Synthesis oftert-Butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane

Step 1: (4-Bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane

4-Bromo-3-methoxyphenol (254 g, 1251 mmol) was dissolved in DCM (2500mL) and treated with DIPEA (437 mL, 2502 mmol) under nitrogenatmosphere. tert-Butylchlorodimethylsilane (198 g, 1314 mmol) was addedand the reaction mixture was stirred at room temperature overnight. Thecrude product was diluted with water and the organic layer was extractedthen dried over sodium sulfate and concentrated.

Step 2:tert-Butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane

Nitrogen was bubbled through a stirred mixture of potassium acetate (392g, 3999 mmol), (4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane (472g, 1250 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (381 g, 1499mmol), DPPF (55.4 g, 100 mmol), and PdCl₂(dppf).CH₂Cl₂ adduct (82 g, 100mmol) in dioxane (4500 mL). The reaction mixture was slowly heated to aninternal temperature of 69° C., then left to stir at 69° C. for 16 hoursbefore being slowly cooled over an hour to 20° C. The reaction mixturewas filtered through celite, rinsed with EtOAc, and the solvent removedin vacuo to afford a black gel. The crude gel was dissolved in DCM,treated with DIPEA (90 mL) and tert-butylchlorodimethylsilane (70 g) andthe resulting mixture left to stir at room temperature overnight. Themixture was diluted with water (1 L) and brine (1 L) and stirred for 30mins. The organic phase was separated, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was absorbedonto silica gel and purified by flash chromatography over silica using20% EtOAc in heptanes (+1% TEA) as the eluent to afford the crudeproduct as a black semi-solid. The crude material was again absorbedonto silica gel and purified by silica flash chromatography using 10%EtOAc in heptanes (+1% TEA) as the eluent to afford the title compoundas an oil.

Intermediate 4:5-Bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of 2,5-dibromo-1,3,4-thiadiazole (2.975 g, 12.2mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (2.493 g, 14.64 mmol)in dioxane (40 mL) was added DIPEA (10.65 mL, 61 mmol) and the resultingmixture refluxed at 120° C. for 16 hours. The reaction mixture wascooled to room temperature then filtered under vacuum, rinsed withdioxane, and the filtrate concentrated in vacuo to afford the crudeproduct as a pink/red oil. The crude material was purified by flashchromatography using 3% [7M NH₃ in MeOH]/DCM as the eluent to afford thetitle compound as a pink/red solid (2.924 g, 72% yield). LC-MS: Rt 0.70min; MS m/z 335.2 [M+2H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm4.13-4.03 (m, 1H), 2.92 (s, 3H), 1.57 (dd, J=12.13, 3.54 Hz, 2H), 1.39(t, J=12.13 Hz, 2H), 1.26 (br. s., 1H), 1.16 (s, 6H), 1.06 (s, 6H).LC-MS: Rt 1.12 min; MS m/z 335.2 [M+H]⁺ [Method B].

By employing the method of Intermediate 4, using appropriate startingmaterials, the following intermediates were prepared:

LCMS M + 1, Rt, Intermediate Compound Method ¹H NMR 400 MHz 5

377.0  1.15 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.70-3.58 (m, 2 H),3.58- 3.45 (m, 2 H), 3.30 (d, J = 12.13 Hz, 2 H), 3.18 (dd, J = 11.12,3.54 Hz, 2 H), 3.02 (br. s., 2 H), 1.39 (s, 9 H) (3aR,6aS)-tert-Butyl 5-(5-bromo-1,3,4- thiadiazol-2- yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate 6

335.2, 0.72 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.08 (tt, J = 12.32,3.35 Hz, 1 H), 2.92 (s, 3 H), 1.57 (dd, J = 12.38, 3.28 Hz, 2 H), 1.39(t, J = 12.13 Hz, 2 H), 1.26 (br. s., 1 H), 1.16 (s, 6 H), 1.06 (s, 6 H)5-Bromo-N-(1,2,2,6,6- pentamethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine

SYNTHESIS OF EXAMPLES Example 1 Synthesis of5-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

To a stirred suspension of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(Intermediate 1) (297 mg, 0.990 mmol) and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (300 mg, 0.900 mmol) in dioxane (4 mL) was addedPd(PPh₃)₄ (52 mg, 0.045 mmol) followed by a solution of Na₂CO₃ (191 mg,1.800 mmol) in water (1 mL). The resulting mixture was purged withnitrogen, sealed, and heated at 120° C. for 30 minutes under microwaveirradiation. The reaction mixture was diluted with EtOAc (100 mL) andwashed with water (50 mL). The organic phase was separated, dried overMgSO₄, and filtered. The filtrate was concentrated in vacuo to affordthe crude product as a yellow oil. The crude material was pre-absorbedonto silica gel and purified by flash chromatography over silica using2.5% [7M NH₃ in MeOH]/DCM as the eluent to afford a pale brownglass-like solid which was re-dissolved in MeOH (10 mL) and SiliaMetSDMT (0.52 mmol/g, 433 mg) was added. The resulting suspension was placedin a shaker for 2.5 hours then the SiliaMetS DMT removed by filtrationand the filtrate concentrated in vacuo to afford an orange/brown oil.The crude oil was re-dissolved in MeOH and loaded onto a 10 g SCXcartridge (pre-wet with MeOH). The cartridge was washed with MeOH (40mL) then flushed with 7M NH₃ in MeOH (40 mL). The MeOH/NH₃ was removedin vacuo to afford a pale orange/brown glass-like solid. The crudeglass-like solid was re-purified by mass directed preparative HPLC underbasic conditions (5 mM NH₄OH) to afford the title compound as a palepink glass-like solid (0.185 g, 48% yield). LC-MS: Rt 1.53 min; MS m/z427.3 [M+H]⁺ [Method B]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (d, J=2.53Hz, 1H), 8.19 (d, J=8.59 Hz, 1H), 7.80 (d, J=1.52 Hz, 1H), 7.65 (d,J=2.02 Hz, 1H), 7.59 (dd, J=8.59, 2.02 Hz, 1H), 6.60 (dd, J=2.53, 1.52Hz, 1H), 4.36 (tt, J=12.38, 3.28 Hz, 1H), 4.04 (s, 3H), 2.99 (s, 3H),1.61 (dd, J=12.13, 3.03 Hz, 2H), 1.42 (t, J=12.38 Hz, 2H), 1.29 (br. s.,1H), 1.22 (s, 6H), 1.09 (s, 6H). HR-MS: Rt 1.54 mins; MS m/z 427.2260[M+H]⁺ [Method C].

By employing the method of Example 1, using appropriate startingmaterials, the following compounds were prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 2

397.2, 0.52 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.97 (br. s., 1 H),8.14-8.11 (m, 1 H), 7.92-7.85 (m, 2 H), 7.76 (d, J = 8.59 Hz, 1 H),7.18-7.11 (m, 2 H), 4.29-4.20 (m, 1 H), 3.01 (s, 3 H), 1.64 (dd, J =12.13, 3.03 Hz, 2 H), 1.44 (t, J = 12.13 Hz, 2 H), 1.22 (s, 6 H), 1.09(s, 6 H) 6-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2- yl)naphthalen-2-ol 3

412.3, 0.60 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.97 (s, 1 H), 8.06(d, J = 7.58 Hz, 1 H), 7.86-7.81 (m, 1 H), 7.73 (td, J = 7.71, 1.26 Hz,1 H), 7.54- 7.46 (m, 1 H), 4.40 (t, J = 12.38 Hz, 1 H), 4.14 (s, 3 H),3.02 (s, 3 H), 1.65 (d, J = 9.60 Hz, 2 H), 1.48 (t, J = 11.87 Hz, 2 H),1.25 (s, 6 H), 1.12 (s, 6 H) 5-(2-Methoxyquinolin-3-yl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 4

411.3, 0.59 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (s, 1 H), 7.97(d, J = 8.08 Hz, 1 H), 7.87 (d, J = 8.08 Hz, 1 H), 7.59-7.49 (m, 2 H),7.41 (td, J = 7.45, 1.26 Hz, 1 H), 4.44 (br. s., 1 H), 4.05 (s, 3 H),3.03 (s, 3 H), 1.80-1.02 (br. m., 16 H) 5-(3- Methoxynaphthalen-2-yl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 5

427.3, 0.55 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.64 (d, J = 2.53 Hz,1 H), 8.19 (d, J = 8.59 Hz, 1 H), 7.80 (d, J = 1.52 Hz, 1 H), 7.65 (d, J= 2.02 Hz, 1 H), 7.59 (dd, J = 8.59, 2.02 Hz, 1 H), 6.63-6.59 (m, 1 H),4.43- 4.32 (m, 1 H), 4.04 (s, 3 H), 2.99 (s, 3 H), 1.63 (d, J = 11.12Hz, 2 H), 1.43 (t, J = 10.11 Hz, 2 H), 1.23 (br. s., 6 H), 1.10 (br. s.,6 H) 5-(2-Methoxy-4-(1H- pyrazol-1-yl)phenyl)-N- (1,2,2,6,6-pentamethylpiperidin-4- yl)-1,3,4-thiadiazol-2- amine

Example 6 Synthesis of5-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Step 1:3-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenol

To a stirred suspension oftert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane(Intermediate 3) (3.28 g, 9.00 mmol) and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (1 g, 6.00 mmol) in dioxane (48 mL) under nitrogen wasadded Pd(PPh₃)₄ (0.347 g, 0.30 mmol) followed by a solution of Na₂CO₃(1.272 g, 12.00 mmol) in water (12 mL). The resulting mixture wasrefluxed at 120° C. for 18 hours. The reaction mixture was cooled toroom temperature, then diluted with EtOAc (150 mL) and washed with water(100 mL). The organic phase was separated and the aqueous phasere-extracted with EtOAc (150 mL). The combined organics were dried overMgSO₄, filtered, and the filtrate concentrated in vacuo to afford anoily brown residue. The residue was suspended in EtOAc (10 mL) andsonicated, then the resulting suspension was filtered under vacuum toafford the crude product as an off-white solid. The crude mixture waspurified by flash chromatography using 3% [7M NH₃ in MeOH]/DCM as theeluent to afford the title compound as a pale yellow glass-like solid(0.534 g, 23% yield). LC-MS: Rt 0.75 min; MS m/z 377.3 [M+H]⁺ [MethodA]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.99 (br. s., 1H), 7.88 (d, J=8.59Hz, 1H), 6.54 (d, J=2.53 Hz, 1H), 6.50 (dd, J=8.34, 2.27 Hz, 1H),4.34-4.25 (m, 1H), 3.86 (s, 3H), 2.94 (s, 3H), 1.59 (dd, J=11.62, 3.03Hz, 2H), 1.40 (t, J=12.38 Hz, 2H), 1.26 (br. s., 1H), 1.20 (s, 6H), 1.08(s, 6H).

Step 2:3-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyltrifluoromethanesulfonate

A stirred suspension of3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenol(533 mg, 1.416 mmol) and TEA (493 μL, 3.540 mmol) in DCM (15 mL) undernitrogen was cooled in an ice bath and1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(531 mg, 1.486 mmol) was added. The resulting mixture was stirred at icebath temperature for 10 minutes, then at room temperature for 18 hours.The reaction mixture was diluted with DCM (35 mL) and washed withsaturated NaHCO_(3(aq)) (20 mL). The organic phase was separated via aphase separator and concentrated in vacuo to afford the crude product asa white solid. The crude product was pre-absorbed onto silica gel andpurified by flash chromatography using a gradient from 0-10% MeOH/DCMover 18 minutes to afford the title compound as a pale yellow solid(0.577 g, 77% yield). LC-MS: Rt 1.12 min; MS m/z 509.3 [M+H]⁺ [MethodA]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (d, J=8.59 Hz, 1H), 7.42 (d,J=2.53 Hz, 1H), 7.21 (dd, J=8.84, 2.27 Hz, 1H), 4.44-4.33 (m, 1H), 4.00(s, 3H), 2.99 (s, 3H), 1.62 (d, J=9.60 Hz, 2H), 1.43 (t, J=11.62 Hz,2H), 1.28 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H).

Step 3:5-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(177 mg, 0.849 mmol) and3-methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenyltrifluoromethanesulfonate (332 mg, 0.653 mmol) in dioxane (4 mL) wasadded Pd(PPh₃)₄ (38 mg, 0.033 mmol) followed by a solution of Na₂CO₃(208 mg, 1.958 mmol) in water (1 mL). The resulting mixture was purgedwith nitrogen, sealed, and heated at 120° C. for 30 minutes undermicrowave irradiation. The reaction mixture was diluted with EtOAc (100mL) and washed with water (50 mL). The organic phase was separated,dried over MgSO₄, and filtered. To the filtrate was added SiliaMetS DMT(541 mg, 0.61 mmol/g, 0.33 mmols) and the resulting suspension stirredat room temperature for 18 hours. The SiliaMetS DMT was removed byvacuum filtration, rinsed with EtOAc, and the filtrate concentrated invacuo to afford the crude product as a pale yellow solid. The crudematerial was recrystallized from MeOH (3 mL) to afford the titlecompound as a white solid (0.166 g, 57% yield). LC-MS: Rt 0.86 min; MSm/z 441.4 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (s,1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.37 (d, J=1.52 Hz, 1H),7.29 (dd, J=8.59, 1.52 Hz, 1H), 4.35 (tt, J=12.38, 3.28 Hz, 1H), 3.99(s, 3H), 3.88 (s, 3H), 2.97 (s, 3H), 1.61 (dd, J=11.87, 3.28 Hz, 2H),1.41 (t, J=12.13 Hz, 2H), 1.26 (s, 1H), 1.21 (s, 6H), 1.09 (s, 6H).LC-MS: Rt 1.60 min; MS m/z 440.4 [M+H]⁺ [Method B]. HR-MS: Rt 1.43 min;MS m/z 441.2419 [M+H]⁺ [Method C].

By employing the method of Example 6, using appropriate startingmaterials, the following compounds were prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 7

427.3, 0.51 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.03 (br. s., 1 H),8.32 (br. s., 1 H), 8.05 (d, J = 8.08 Hz, 2 H), 7.41 (d, J = 1.52 Hz, 1H), 7.34 (dd, J = 8.08, 1.52 Hz, 1 H), 4.35 (tt, J = 12.44, 2.97 Hz, 1H), 4.00 (s, 3 H), 2.98 (s, 3 H), 1.61 (dd, J = 11.87, 3.28 Hz, 2 H),1.47-1.36 (m, 2 H), 1.27 (br. s., 1 H), 1.21 (s, 6 H), 1.09 (s, 6 H)5-(2-Methoxy-4-(1H- pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2- amine 8

468.4, 0.48 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.19 (d, J = 8.08 Hz,1 H), 7.80 (d, J = 7.07 Hz, 1 H), 7.48 (d, J = 1.52 Hz, 1 H), 7.44 (dd,J = 8.08, 1.52 Hz, 1 H), 6.83 (d, J = 2.02 Hz, 1 H), 6.67 (dd, J = 7.07,2.02 Hz, 1 H), 4.44-4.34 (m, 1 H), 4.05 (s, 3 H), 3.47 (s, 3 H), 2.99(s, 3 H), 1.61 (dd, J = 12.13, 3.03 Hz, 2 H), 1.42 (t, J = 12.13 Hz, 2H), 1.28 (br. s., 1 H), 1.22 (s, 6 H), 1.09 (s, 6 H) 4-(3-Methoxy-4-(5-(methyl(2,2,6,6- tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2-yl)phenyl)-1- methylpyridin-2(1H)-one 9

454.4, 0.46 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.93 (br, s, 1 H),8.10 (d, J = 8.08 Hz, 1 H), 7.95 (dd, J = 9.60, 3.03 Hz, 1 H), 7.89 (d,J = 2.53 Hz, 1 H), 7.35 (d, J = 1.52 Hz, 1 H), 7.29 (dd, J = 8.34, 1.77Hz, 1 H), 6.45 (d, J = 9.60 Hz, 1 H), 4.42-4.33 (m, 1 H), 4.02 (s, 3 H),2.98 (s, 3 H), 1.63 (d, J = 9.09 Hz, 2 H), 1.44 (t, J = 11.12 Hz, 2 H),1.23 (s, 6 H), 1.10 (s, 6 H) 5-(3-Methoxy-4-(5- (methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4- thiadiazol-2-yl)phenyl)pyridin-2-ol 10

468.4, 0.48 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (d, J = 2.53 Hz,1 H), 8.12 (d, J = 8.08 Hz, 1 H), 7.95 (dd, J = 9.35, 2.78 Hz, 1 H),7.37 (d, J = 1.52 Hz, 1 H), 7.31 (dd, J = 8.34, 1.77 Hz, 1 H), 6.51 (d,J = 9.60 Hz, 1 H), 4.41-4.32 (m, 1 H), 4.03 (s, 3 H), 3.53 (s, 3 H),2.98 (s, 3 H), 1.61 (dd, J = 11.87, 3.28 Hz, 2 H), 1.42 (t, J = 12.13Hz, 2 H), 1.27 (br. s., 1 H), 1.21 (s, 6 H), 1.09 (s, 6 H)5-(3-Methoxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4- thiadiazol-2-yl)phenyl)-1- methylpyridin-2(1H)-one 11

425.4, 0.49 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.21 (s, 1 H), 7.92(s, 1 H), 7.57 (s, 1 H), 7.54-7.46 (m, 2 H), 4.34-4.24 (m, 1 H), 3.87(s, 3 H), 2.99 (s, 3 H), 2.53 (s, 3 H), 1.69- 1.57 (m, 2 H), 1.44 (t, J= 11.87 Hz, 2 H), 1.21 (s, 6 H), 1.10 (s, 6 H) N-Methyl-5-(2-methyl-4-(1-methyl-1H-pyrazol-4- yl)phenyl)-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2- amine 12

522.3, 0.51 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (d, J = 8.59 Hz,1 H), 7.91 (dd, J = 8.34, 1.77 Hz, 1 H), 7.85- 7.81 (m, 2 H), 6.81 (d, J= 2.02 Hz, 1 H), 6.65 (dd, J = 7.07, 2.02 Hz, 1 H), 4.36-4.27 (m, 1 H),3.47 (s, 3 H), 3.04 (s, 3 H), 1.65 (d, J = 11.62 Hz, 2 H), 1.52-1.40 (m,2 H), 1.21 (br. s., 6 H), 1.10 (br. s., 6 H) 1-Methyl-4-(4-(5-(methyl(2,2,6,6- tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2-yl)-3- (trifluoromethoxy)phenyl) pyridin-2(1H)-one 13

329.2, 0.47 min, D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.37 (br. s., 1 H),8.10 (d, J = 8.08 Hz, 1 H), 7.06 (s, 1 H), 7.04-7.00 (m, 1 H), 4.41-4.32(m, 1 H), 3.96 (s, 3 H), 2.98 (s, 3 H), 2.29 (br. s., 3 H), 2.24 (br.s., 3 H), 1.62 (d, J = 10.61 Hz, 2 H), 1.42 (t, J = 11.62 Hz, 2 H), 1.27(br. s., 1 H), 1.22 (s, 6 H), 1.09 (s, 6 H) 5-(4-(3,5-Dimethyl-1H-pyrazol-4-yl)-2- methoxyphenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2- amine 14

479.4, 0.50 min, D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.27 (s, 1 H), 8.05(d, J = 8.08 Hz, 1 H), 7.98 (s, 1 H), 7.37 (d, J = 1.52 Hz, 1 H), 7.29(dd, J = 8.59, 1.52 Hz, 1 H), 4.35 (tt, J = 12.38, 3.28 Hz, 1 H), 3.99(s, 3 H), 3.88 (s, 3 H), 2.97 (s, 3 H), 1.61 (dd, J = 11.87, 3.28 Hz, 2H), 1.41 (t, J = 12.13 Hz, 2 H), 1.26 (s, 1 H), 1.21 (s, 6 H), 1.09 (s,6 H) 5-(2-Methoxy-4-(1- methyl-1H-pyrazol-4- yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2- amine

Example 15 Synthesis of2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol

To a stirred solution of5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(129 mg, 0.293 mmol) in NMP (3 mL) was added Na₂CO₃ (47 mg, 0.439 mmol)followed by PhSH (35 μL, 0.337 mmol). The resulting mixture was sealed,evacuated and back filled with nitrogen (×3), then heated at 190° C. for20 minutes under microwave irradiation. The reaction mixture was dilutedwith MeOH (10 mL) and filtered through celite. The filtrate wasacidified by addition of acetic acid (3 mL) and loaded onto a 2 g SCXcartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15mL) and flushed with 7M NH₃ in MeOH (15 mL). The MeOH/NH₃ was removed invacuo to afford the crude product as a brown solid. The crude materialwas purified by UV-directed preparative HPLC under basic (5 mM NH₄OH)conditions, collecting at 352 nm, to afford the title compound as a palebrown glass-like solid (0.096 g, 77% yield). LC-MS: Rt 0.88 min; MS m/z427.2 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.13 (s, 1H),7.86-7.78 (m, 2H), 7.17-7.10 (m, 2H), 4.35-4.25 (m, 1H), 3.87 (s, 3H),2.99 (s, 3H), 1.62 (dd, J=11.87, 3.28 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H),1.21 (s, 6H), 1.09 (s, 6H). LC-MS: Rt 1.69 min; MS m/z 427.4 [M+H]⁺[Method B]. HR-MS: Rt 1.49 mins; MS m/z 427.2660 [M+H]⁺ [Method C].

By employing the methods of Example 6 and 15, using appropriate startingmaterials, the following compounds were prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 16

413.3, 0.55 min D ¹H NMR (400 MHz, DMSO-d₆) 5 ppm 8.47 (d, J = 2.02 Hz,1 H), 7.99 (d, J = 8.59 Hz, 1 H), 7.78-7.73 (m, 1 H), 7.47 (d, J = 1.52Hz, 1 H), 7.36 (d, J = 8.59 Hz, 1 H), 6.58-6.53 (m, 1 H), 4.33 (t, J =12.13 Hz, 1 H), 2.99 (s, 3 H), 1.69-1.58 (m, 2 H), 1.47 (t, J = 12.13Hz, 2 H), 1.23 (s, 6 H), 1.12 (s, 6 H) 2-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4- thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol 17

454.4, 0.47 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.16 (d, J = 2.53 Hz,1 H), 7.88 (d, J = 8.08 Hz, 1 H), 7.79 (dd, J = 9.35, 2.78 Hz, 1 H),7.19-7.12 (m, 2 H), 6.49 (d, J = 9.09 Hz, 1 H), 4.37-4.28 (m, 1 H), 3.51(s, 3 H), 3.00 (s, 3 H), 1.69-1.58 (m, 2 H), 1.54-1.37 (m, 2 H), 1.23(s, 6 H), 1.11 (br. s., 6 H) 5-(3-Hydroxy-4-(5- (methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4- thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)- one 18

454.3, 0.48 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.00 (d, J = 8.08 Hz,1 H), 7.77 (d, J = 7.07 Hz, 1 H), 7.27-7.20 (m, 2 H), 6.61 (d, J = 2.02Hz, 1 H), 6.51 (dd, J = 7.07, 2.02 Hz, 1 H), 4.40- 4.29 (m, 1 H), 3.45(s, 3 H), 3.00 (s, 3 H), 1.66-1.60 (m, 2 H), 1.45 (t, J = 11.87 Hz, 2H), 1.22 (s, 6 H), 1.10 (s, 6 H) 4-(3-Hydroxy-4-(5- (methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4- thiadiazol-2-yl)phenyl)-1-methylpyridin-2(1H)- one 19

440.4, 0.45 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.83 (br. s., 1 H),7.88 (d, J = 8.59 Hz, 1 H), 7.80 (dd, J = 9.60, 2.53 Hz, 1 H), 7.71 (d,J = 2.02 Hz, 1 H), 7.16-7.09 (m, 2 H), 6.44 (d, J = 9.60 Hz, 1 H),4.36-4.27 (m, 1 H), 2.99 (s, 3 H), 1.67-1.59 (m, 2 H), 1.50-1.37 (m, 2H), 1.22 (s, 6 H), 1.10 (s, 6 H) 5-(3-Hydroxy-4-(5- (methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4- thiadiazol-2-yl)phenyl)pyridin-2-ol

Example 20 Synthesis of3-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalene-2,7-diol

Step 1:7-(Benzyloxy)-6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen-2-ol

To a stirred solution of7-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol(73 mg, 0.195 mmol) and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (84 mg, 0.150 mmol) in dioxane (2 mL) was addedPd(PPh₃)₄ (3.5 mg, 0.003 mmol) followed by a solution of Na₂CO₃ (63 mg,0.599 mmol) in water (0.5 mL). The resulting mixture was purged withnitrogen, sealed, and heated at 120° C. for 1 hr under microwaveirradiation. The reaction mixture was diluted with MeOH (20 mL),filtered via syringe filter, and the filtrate concentrated in vacuo toafford the crude product.

The crude mixture was pre-absorbed onto silica gel and purified over a12 g silica cartridge using an ISCO CombiFlash system running a gradientfrom 0-10% MeOH/DCM over 15 minutes. The relevant fractions werecombined and concentrated in vacuo to afford the title compound as ayellow glass-like solid product (51 mg, 67.8% yield). LC-MS: Rt 1.04min; MS m/z 503.4 [M+H]+[Method B]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.92(s, 1H) 8.53 (s, 1H) 7.81 (d, J=9.09 Hz, 1H) 7.56-7.63 (m, 2H) 7.32-7.48(m, 4H) 7.08 (d, J=2.53 Hz, 1H) 6.97 (dd, J=8.84, 2.27 Hz, 1H) 5.33 (s,2H) 3.92 (br. s., 1H) 2.94 (s, 3H) 1.69-0.97 (br. m., 16H).

Step 2:3-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalene-2,7-diol

To a stirred, ice-bath cooled suspension of7-(benzyloxy)-6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)naphthalen-2-ol(49 mg, 0.112 mmol) in DCM (2 ml) under nitrogen was added BBr₃ (1Msolution in DCM, 0.56 mL, 0.56 mmol). The reaction mixture was quenchedby addition of MeOH (2 mL) and the resulting solution was warmed to roomtemperature, then loaded onto a 1 g SCX cartridge (pre-wet with MeOH).The cartridge was washed with MeOH (˜15 mL) then flushed with 7M NH₃ inMeOH (˜10 mL). The MeOH/NH₃ was removed in vacuo to afford the crudeproduct. The crude product was taken up in 1:1 MeOH:DMSO (2 mL),filtered via syringe filter, and the filtrate purified by preparativeHPLC, under neutral conditions, running a gradient from 10-90%MeCN/water over 15 minutes. The relevant fractions were combined andconcentrated in vacuo to afford the title compound as a dark green/brownsolid (20.6 mg, 49.2% yield). LC-MS: Rt 0.85 min; MS m/z 413.3 [M+H]⁺[Method B]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.92 (br. s., 1H) 9.81 (br.s., 1H) 8.31 (s, 1H) 7.74 (d, J=9.09 Hz, 1H) 7.07 (s, 1H) 6.87-6.94 (m,2H) 4.25-4.34 (m, 1H) 3.01 (s, 3H) 1.64 (dd, J=12.13, 3.03 Hz, 2H) 1.45(t, J=12.13 Hz, 2H) 1.22 (s, 6H) 1.10 (s, 6H).

By employing the method of Example 20, using appropriate startingmaterials, the following compounds were prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 21

355.1, 0.44 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.34 (s, 1 H), 7.75(d, J = 9.09 Hz, 1 H), 7.07 (s, 1 H), 6.95-6.86 (m, 2 H), 3.70 (dd, J =9.85, 6.82 Hz, 2 H), 3.33-3.26 (m, 2 H), 2.98- 2.85 (m, 4 H), 2.70 (d, J= 8.08 Hz, 2 H) 3-(5-((3aR,6aS)- Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4- thiadiazol-2- yl)naphthalene-2,7-diol 22

397.3, 0.60 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.08 (br. s., 1 H),8.76 (d, J = 12.13 Hz, 1 H), 8.55 (s, 1 H), 7.91 (d, J = 8.08 Hz, 1 H),7.82-7.72 (m, 2 H), 7.48-7.43 (m, 1 H), 7.37- 7.31 (m, 2 H), 4.63-4.53(m, 1 H), 3.08 (s, 3 H), 2.03-1.90 (m, 4 H), 1.50 (s, 6 H), 1.45 (s, 6H) 3-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2- yl)naphthalen-2-ol•HBr 23

398.3, 0.52 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.38 (br. s., 1 H),8.80 (s, 1 H), 7.89 (d, J = 7.07 Hz, 1 H), 7.62- 7.56 (m, 1 H), 7.41 (d,J = 8.59 Hz, 1 H), 7.27 (t, J = 7.58 Hz, 1 H), 4.41- 4.31 (m, 1 H), 3.00(s, 3 H), 1.68- 1.55 (m, 2 H), 1.44 (t, J = 11.62 Hz, 2 H), 1.23 (s, 6H), 1.10 (s, 6 H) 3-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4- thiadiazol-2-yl)quinolin- 2-ol 24

413.3, 0.55 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.37 (d, J = 2.02 Hz,1 H), 8.33 (d, J = 3.03 Hz, 1 H), 7.72-7.64 (m, 2 H), 7.04 (d, J = 8.59Hz, 1 H), 6.50 (t, J = 2.02 Hz, 1 H), 4.38-4.29 (m, 1 H), 3.00 (s, 3 H),1.64 (dd, J = 11.62, 3.03 Hz, 2 H), 1.45 (t, J = 12.13 Hz, 2 H), 1.22(s, 6 H), 1.10 (s, 6 H) 2-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4- thiadiazol-2-yl)-4-(1H- pyrazol-1-yl)phenol

Example 25 Synthesis of5-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Step 1: 5-(4-Bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine

A stirred mixture of 4-bromo-2-chlorobenzoic acid (2 g, 8.49 mmol) andhydrazinecarbothioamide (1.161 g, 12.74 mmol) was cooled under nitrogenin an ice-bath. POCl₃ (2.375 mL, 25.5 mmol) was then added dropwise. Oncompletion of addition, the reaction mixture was warmed to 78° C. andleft to stir for 3 hours. The reaction mixture was allowed to cool toroom temperature then cooled further in an ice-bath. Quenching byaddition of ice-water (50 mL) resulted in a solid/gum-like mass. Thismaterial was sonicated for 1.5 hours and the resulting suspension wasdiluted with a further 50 mL water and slurried for 16 hours. Thesuspension was filtered under vacuum and the solid rinsed with water,then re-suspended in saturated NaHCO_(3(aq)) (100 mL). The suspensionwas slurried for 30 minutes then filtered under vacuum and rinsed withwater to afford the crude product as an off-white solid. The crudeproduct was pre-absorbed onto silica gel and purified by flashchromatography using a gradient from 0-10% MeOH/DCM over 30 minutes toafford the title compound as a pale yellow/off-white solid (1.087 g, 44%yield). LC-MS: Rt 1.09 min; MS m/z 292.0 [M+2H]⁺ [Method A]. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.96 (d, J=8.59 Hz, 1H), 7.91 (d, J=2.02 Hz, 1H),7.68 (dd, J=8.59, 2.02 Hz, 1H), 7.51 (s, 2H).

Step 2: 2-Bromo-5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazole

5-(4-Bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (1.087 g, 3.74 mmol)was added, portionwise over 5 minutes, to a stirred solution of CuBr₂ (1g, 4.49 mmol) and t-BuNO₂ (0.661 mL, 5.61 mmol) in MeCN (11 mL) undernitrogen. On completion of addition, the reaction mixture was stirred atroom temperature for 18 hours. The reaction mixture was quenched byaddition of saturated NH₄Cl_((aq)) (40 mL) and extracted with EtOAc (100mL). The organic phase was separated, dried over MgSO₄, and filtered.The filtrate was concentrated in vacuo to afford the title compound as abrown solid (1.193 g, 90% yield) with no further purification necessary.LC-MS: Rt 1.51 mins; MS m/z 354.8 M+; [Method A]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.12 (d, J=8.59 Hz, 1H), 8.07 (d, J=2.02 Hz, 1H), 7.80(dd, J=8.59, 2.02 Hz, 1H).

Step 3:5-(4-Bromo-2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

A stirred solution of2-bromo-5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazole (700 mg, 1.975mmol) and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (1009 mg, 5.92 mmol) in NMP (4 mL) was heated to 120°C. for 3 hours. The reaction mixture was allowed to cool to roomtemperature then diluted with DCM (100 mL) and washed with saturatedNaHCO_(3(aq)) (100 mL). The organic phase was separated, dried overMgSO₄, and filtered. The filtrate was concentrated in vacuo to a brownliquid. The crude material was purified by silica flash chromatography,running a gradient from 0-10% [2M NH₃ in MeOH]/DCM over 30 minutes,collecting at 320 nm to afford the title compound as a light brownglass-like solid (750 mg, 86% yield). LC-MS: Rt 1.10 min; MS m/z 445.1[M+2H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.96 (d, J=8.59 Hz,1H), 7.93 (d, J=2.02 Hz, 1H), 7.70 (dd, J=8.59, 2.02 Hz, 1H), 4.36 (tt,J=12.38, 3.28 Hz, 1H) 3.01 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H),1.43 (t, J=12.13 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).

Step 4:5-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(129 mg, 0.620 mmol) and5-(4-bromo-2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(250 mg, 0.563 mmol) in dioxane (4 mL) was added Pd(PPh₃)₄ (33 mg, 0.028mmol), followed by a solution of Na₂CO₃ (179 mg, 1.69 mmol) in water (1mL). The reaction mixture was purged with nitrogen, sealed, and heatedat 80° C. for an hour under microwave irradiation. The reaction mixturewas diluted with EtOAc (50 mL) and washed with saturated NaHCO_(3(aq))(25 mL). The organic phase was separated, dried over MgSO₄, andfiltered. The filtrate was concentrated in vacuo to afford the crudeproduct as a brown solid. The crude material was taken up in a 2:1mixture of MeOH:DMSO (4.5 mL), passed through a syringe filter, andpurified by UV-directed preparative HPLC under basic conditions (5 mMNH₄OH), collecting at 335 nm to afford the title compound as a whitesolid (138 mg, 55% yield). LC-MS: Rt 0.90 min; MS m/z 445.3 [M+H]⁺[Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.32 (s, 1H), 8.02 (s, 1H),7.99 (d, J=8.08 Hz, 1H), 7.84 (d, J=1.52 Hz, 1H), 7.67 (dd, J=8.08, 1.52Hz, 1H), 4.36 (tt, J=12.44, 3.47 Hz, 1H), 3.88 (s, 3H), 3.01 (s, 3H),1.62 (dd, J=11.87, 3.28 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.28 (br. s.,1H), 1.21 (s, 6H), 1.09 (s, 6H). LC-MS: Rt 1.84 mins; MS m/z 444.8 M⁺[Method B].

Example 26 Synthesis of3-Chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol

Step 1:3-Chloro-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol

To a stirred solution of5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Example 25) (125 mg, 0.281 mmol) in 1:1 AcOH:Ac₂O (2.8 mL) was addedPhI(OAc)₂ (127 mg, 0.393 mmol) followed by Pd(OAc)₂ (6 mg, 0.028 mmol).The reaction mixture was warmed to 80° C. and stirred for 48 hours. Thereaction mixture was cooled to room temperature, then diluted with MeOH(10 mL) and loaded onto a 2 g SCX cartridge (pre-wet with MeOH). Thecartridge was washed with MeOH (10 mL) then flushed with 7M NH₃ in MeOH(10 mL). The MeOH/NH₃ was removed in vacuo to afford the crude productas a brown glass-like solid. The crude material was taken up in MeOH (3mL), passed through a syringe filter, and purified by mass-directedpreparative HPLC under basic conditions (5 mM NH₄OH) to give the crudeproduct as a brown glass-like solid. The crude solid was re-dissolved inMeOH (3 mL) and re-purified by UV-directed preparative HPLC under acidicconditions (0.1% TFA), collecting at 348 nm. The combined fractions wereloaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridgewashed with MeOH (10 mL) then flushed with 7M NH₃ in MeOH (10 mL). TheMeOH/NH₃ was removed in vacuo to afford the title compound as anoff-white glass-like solid (6 mg, 5% yield). LC-MS: Rt 0.52 mins; MS m/z461.3/463.2 [M+H]⁺ [Method D]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.26 (s,1H), 7.95 (s, 1H), 7.32 (s, 1H), 7.15 (d, J=1.52 Hz, 1H), 4.35 (br. s.,1H), 3.87 (s, 3H), 3.01 (s, 3H), 1.65 (d, J=9.60 Hz, 2H), 1.48 (br. s.,2H), 1.22 (br. s., 6H), 1.11 (br. s., 6H).

By employing the method of Example 25, using appropriate startingmaterials, the following compounds were prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 27 LPE765

431.1, 0.87 min D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.12 (br. s., 1 H),8.24 (br. s., 2 H), 7.99 (d, J = 8.08 Hz, 1 H), 7.90 (d, J = 1.52 Hz, 1H), 7.76-7.67 (m, 1 H), 4.38 (t, J = 12.13 Hz, 1 H), 3.01 (s, 3 H),1.73-1.58 (m, 2 H), 1.47 (t, J = 12.13 Hz, 2 H), 1.23 (s, 6 H), 1.11 (s,6 H) 5-(2-chloro-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)- N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2- amine

Example 28 Synthesis of 3-Methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(5-methyloxazol-2-yl)phenol

Step 1:5-(2-(Benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)boronic acid(Intermediate 2) (56 mg, 0.165 mmol) and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (50 mg, 0.150 mmol) in dioxane (1 mL) was addedPd(PPh₃)₄ (9 mg, 0.008 mmol), followed by a solution of Na₂CO₃ (32 mg,0.300 mmol) in water (0.25 mL). The resulting mixture was purged withnitrogen, sealed, and heated at 120° C. for 30 minutes under microwaveirradiation. The reaction mixture was diluted with MeOH (20 mL),filtered via syringe filter, and the filtrate concentrated in vacuo toafford the crude product as a pink/red oily residue. The crude materialwas purified by UV-directed preparative HPLC under acidic conditions(0.1% TFA), collecting at 311 nm to afford the TFA salt of the titlecompound as a yellow glass-like solid. The TFA salt was re-dissolved inMeOH and loaded onto a 1 g SCX cartridge (pre-wet with MeOH). Thecartridge was washed with MeOH (15 mL) then flushed with 7M NH₃ in MeOH(10 mL). The MeOH/NH₃ was removed in vacuo to afford the title compoundas a clear glass-like solid (0.029 g, 35% yield). LC-MS: Rt 2.23 min; MSm/z 548.4 [M+H]⁺ [Method B]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.43-7.25(m, 7H), 7.06 (s, 1H), 5.26 (s, 2H), 4.18-4.10 (m, 1H), 3.85 (s, 3H),2.97 (s, 3H), 2.42 (s, 3H), 1.65-1.56 (m, 2H), 1.50-1.38 (m, 2H), 1.18(s, 6H), 1.09 (s, 6H).

Step 2:3-Methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(5-methyloxazol-2-yl)phenol

A solution of5-(2-(benzyloxy)-6-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(28.9 mg, 0.053 mmol) in 1:1 EtOAc:MeOH (5 mL) was added to a nitrogenflushed flask containing 10% Pd/C (2.9 mg, 10% by weight) and theresulting mixture placed under a hydrogen atmosphere and left to stir atroom temperature for 72 hours. The reaction mixture was purged withnitrogen, diluted with EtOAc (10 mL), filtered through celite, thenrinsed with EtOAc (50 mL). The filtrate was concentrated in vacuo toafford the crude product as a pale yellow solid. The crude material waspurified by preparative HPLC under acidic conditions running a gradientfrom 20-95% MeCN/water (+0.1% TFA) over 15 minutes. The productcontaining fractions were loaded directly onto a 1 g SCX cartridge(pre-wet with MeOH) and the cartridge was washed with MeOH (10 mL) thenflushed with 7M NH₃ in MeOH (10 mL). The MeOH/NH₃ was removed in vacuoto afford the title compound as an off-white/pale brown solid (9 mg, 39%yield). LC-MS: Rt 2.08 min; MS m/z 458.4 [M+H]⁺ [Method B]. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.74 (br. s., 1H), 7.15 (s, 2H), 7.05 (d, J=1.01Hz, 1H), 4.42-4.33 (m, 1H), 4.04 (s, 3H), 3.03 (s, 3H), 2.41 (d, J=1.01Hz, 3H), 1.64 (dd, J=11.87, 3.28 Hz, 2H), 1.44 (t, J=12.13 Hz, 2H), 1.22(s, 6H), 1.09 (s, 6H).

Example 29 Synthesis of2-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4-thiadiazole

Step 1: tert-Butyl4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a 5 mL microwave vial was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(247 mg, 0.8 mmol), 2,5-dibromo-1,3,4-thiadiazole (98 mg, 0.4 mmol),K₃PO₄ (212 mg, 1.0 mmol), Pd(PPh₃)₄ (23 mg, 0.02 mmol), 1,4-dioxane (2mL), and water (0.4 mL). The mixture was purged with N₂ for 10 min, thenheated to 100° C. in the microwave for 1 hour. The mixture was dilutedwith EtOAc, washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by column chromatography(EtOAc/Heptane) to afford 64 mg (46%) of tert-butyl4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate:MS (M+2)=348.1; ¹H NMR (400 MHz, CHLOROFORM-d) δ 6.46 (td, J=3.0, 1.9Hz, 1H), 4.15 (d, J=3.0 Hz, 2H), 3.64 (t, J=5.6 Hz, 2H), 2.73 (m, 2H),1.49 (s, 9H).

Step 2: tert-Butyl4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a 5 mL microwave vial was added tert-butyl4-(5-bromo-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(100 mg, 0.29 mmol),1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole(173 mg, 0.58 mmol), K₃PO₄ (153 mg, 0.72 mmol), and Pd(PPh₃)₄ (17 mg,0.015 mmol), 1,4-dioxane (2 mL), and water (0.4 mL). The mixture waspurged with N₂ for 10 min and heated to 100° C. in the microwave for 1hour. The mixture was diluted with EtOAc, washed with water and brine,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby column chromatography (EtOAc/Heptane) to give 87 mg (68.5%) oftert-butyl4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate:MS (M+1)=440.4; ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.57 (d, J=8.59 Hz,1H), 8.03 (d, J=2.53 Hz, 1H), 7.78 (d, J=1.52 Hz, 1H), 7.62 (d, J=2.02Hz, 1H), 7.32 (dd, J=2.02, 8.59 Hz, 1H), 6.59 (m, 1H), 6.51-6.55 (m,1H), 4.15-4.22 (m, 2H), 4.11 (s, 3H), 3.69 (t, J=5.56 Hz, 2H), 2.78-2.90(m, 2H), 1.51 (s, 9H).

Step 3:2-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4-thiadiazole

To a solution of tert-butyl4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(80 mg, 0.18 mmol) in 1,4-dioxane (1 mL) was added 4 M HCl in1,4-dioxane (0.9 mL). The mixture was stirred for 1 h. The mixture wasthen diluted with MeOH, loaded on the SCX, washed with MeOH, eluted with2 N NH₃ in MeOH, and concentrated in vacuo. The residue was purified bycolumn chromatography (CH₂Cl₂/MeOH) to give 32 mg of2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-1,3,4-thiadiazole:HRMS (M+1) calcd. for C17H17N5OS 340.1232, found 340.1228; ¹H NMR (400MHz, DMSO-d₆) δ 8.71 (d, J=2.53 Hz, 1H), 8.40 (d, J=8.59 Hz, 1H), 7.83(d, J=1.52 Hz, 1H), 7.73 (d, J=2.02 Hz, 1H), 7.68 (dd, J=2.02, 8.59 Hz,1H), 6.73 (m, 1H), 6.54-6.68 (m, 1H), 4.12 (s, 3H), 3.52 (m, 2H), 3.02(t, J=5.81 Hz, 2H), 2.62 (m, 2H).

Example 30 Synthesis of2-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol

Step 1: tert-Butyl4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

DIPEA (430 μL, 2.460 mmol) was added to a stirred solution of2,5-dibromo-1,3,4-thiadiazole (300 mg, 1.230 mmol) and tert-butylpiperazine-1-carboxylate (275 mg, 1.476 mmol) in dioxane (4 mL). Thereaction mixture was heated at 120° C. for 2 hours. The reaction mixturewas cooled to room temperature, filtered under vacuum, rinsed withdioxane, and the filtrate was concentrated in vacuo to afford the crudeproduct as an orange oily residue. The crude material was purified bypreparative HPLC under neutral conditions (ammonium formate modified) toafford the title compound as a yellow solid (331 mg, 77% yield). LC-MS:Rt 1.18 min; MS m/z 351.1 [M+2]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δppm 3.38-3.55 (m, 8H), 1.41 (s, 9H).

Step 2: tert-Butyl4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred suspension of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole[Intermediate 1](132 mg, 0.441 mmol) and tert-butyl4-(5-bromo-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (140 mg, 0.401mmol) in dioxane (2 mL) was added Pd(PPh₃)₄ (23 mg, 20 μmol) followed bya solution of Na₂CO₃ (85 mg, 0.802 mmol) in water (0.5 mL). The reactionmixture was purged with nitrogen, sealed, and heated at 120° C. for 30minutes under microwave irradiation. The reaction mixture was cooled toroom temperature, diluted with DCM (20 mL), washed with water (10 mL),then the organic phase was separated and concentrated in vacuo to affordthe crude product as a pale brown solid. The crude material was purifiedby flash chromatography using a 12 g silica cartridge running anEtOAc/heptane gradient to afford the title compound as a paleyellow/off-white solid (138 mg, 78% yield). LC-MS: Rt 1.34 min; MS m/z443.3 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.65 (d, J=2.53Hz, 1H), 8.21 (d, J=8.59 Hz, 1H), 7.80 (d, J=1.52 Hz, 1H), 7.66 (d,J=2.02 Hz, 1H), 7.60 (dd, J=8.59, 2.02 Hz, 1H), 6.59-6.62 (m, 1H), 4.05(s, 3H), 3.51 (s, 8H), 1.43 (s, 9H).

Step 3:2-(5-(Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol

BBr₃ (1M solution in heptane, 1.56 mL, 1.56 mmol) was added to astirred, nitrogen flushed solution of tert-butyl4-(5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate(138 mg, 0.312 mmol) in DCM (6 mL) and the resulting bright yellowsuspension was stirred at room temperature for 16 hours. The reactionmixture was quenched by addition of MeOH (10 mL) to give a suspension.The solid was collected by vacuum filtration, rinsed with MeOH, andre-dissolved in a mixture of DMSO and water. The solution was loadedonto a 5 g SCX cartridge (pre-wet with MeOH) and the cartridge waswashed with DMSO/water (5 mL), MeOH (20 mL), then flushed with 7M NH₃ inMeOH (30 mL). The MeOH/NH₃ was removed in vacuo to afford the crudeproduct as an off-white solid. The crude material was sonicated in MeOH(5 mL) and the resulting suspension filtered under vacuum to aford thetitle compound as an off-white solid (69 mg, 68% yield). LC-MS: Rt 0.76min; MS m/z 329.2 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.50 (d, J=2.53 Hz, 1H), 8.03 (d, J=8.59 Hz, 1H), 7.77 (d, J=1.52 Hz,1H), 7.52 (d, J=2.02 Hz, 1H), 7.42 (dd, J=8.59, 2.02 Hz, 1H), 6.55-6.61(m, 1H), 3.42-3.48 (m, 4H), 2.80-2.91 (m, 4H).

Example 31 Synthesis of5-(7-Methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Step 1: 6-Bromo-7-methoxyquinoline

In a 100 mL round-bottom flask, a solution of concentrated sulfuric acid(2.1 mL, 39.6 mmol) in water (2.4 mL) was treated with3-nitrobenzenesulfonic acid (2.06 g, 10.1 mmol) and glycerol (2.5 mL,34.8 mmol) to give a thick grey suspension. The mixture was heated to110° C. (oil bath) and 4-bromo-3-methoxyaniline (1.952 g, 9.66 mmol) wasadded portion-wise, resulting in an immobile slurry. Additional portionsof water (3 mL), glycerol (3 mL), and concentrated sulfuric acid (3 mL)were added and the temperature increased to 140° C. After three hoursthe mixture had become a homogeneous dark brown solution, and LCMSanalysis indicated reaction completion. The solution was cooled to RT,poured onto ice, and the pH was adjusted to 8 by addition ofconcentrated (30%) aqueous ammonium hydroxide. The mixture waspartitioned between ethyl acetate and water, washed with water, brine,dried over magnesium sulfate and concentrated to a brown liquid.Purification by flash column chromatography (24 g silica gel, gradientof 0-20% ethyl acetate in dichloromethane over 25 column volumes)provided 6-bromo-7-methoxyquinoline (1.18 g, 46.2%) as a light brownfluffy solid. ¹H NMR (400 MHz, CHLOROFORM-d) ppm 8.86 (dd, J=4.0, 1.5Hz, 1H), 8.01-8.12 (m, 2H), 7.53 (s, 1H), 7.34 (dd, J=8.1, 4.5 Hz, 1H),4.07 (s, 3H). NMR indicates the presence of about 10%7-methyoxyquinoline. The mixture was taken on without furtherpurification.

-   Step 2: (7-Methoxyquinolin-6-yl)boronic acid

To a solution of 6-bromo-7-methoxyquinoline (90% purity, 0.65 g, 2.73mmol) cooled to −78° C. was added drop-wise nBuLi (1.6 M in heptanes,1.877 mL, 3.00 mmol). The solution was stirred for 0.5 h after whichtime trimethyl borate (0.763 mL, 6.83 mmol) was added in a singleportion. The solution was allowed to warm slowly to RT overnight. Thecrude reaction mixture was rotovapped to dryness, concentrated fromheptane (2×), triturated with diethyl ether (3×) and concentrated toprovide a crude mixture of (7-methoxyquinolin-6-yl)boronic acid as a tancolored solid (1.185 g, 214%). LCMS is clean, and based on the recoveredmass the mixture was used without further purification assuming ˜50%purity by weight. MS=204.1 (M+1). ¹H NMR (400 MHz, METHANOL-d₄) ppm 8.48(br s, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.85 (s, 1H), 7.16 (dd, J=8.1, 4.5Hz, 1H), 7.11 (s, 1H), 3.82 (s, 3H).

Step 3:5-(7-Methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

In a microwave tube, a mixture of5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (100 mg, 0.300 mmol), (7-methoxyquinolin-6-yl)boronicacid (˜50% by weight, 171 mg, 0.420 mmol) and sodium carbonate (95 mg,0.90 mmol) in 3:1 dimethoxyethane/water (2.5 mL) was degassed with a drystream of nitrogen for five minutes.Tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.030 mmol) was addedand the mixture heated in a microwave at 140° C. for 30 min. The mixturewas diluted with water and extracted with DCM (6×). HCl in dioxane (1 M,1.2 mL, 1.2 mmol) was added and the solution concentrated to dryness.SCX purification (2 g column, 7 M ammonia in MeOH elution) provided abrown residue which was further purified by flash column chromatography(12 g silica gel, 1-17% 1.4 N ammonia in MeOH gradient in DCM over 30column volumes) to provide5-(7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amineas a yellow solid (104 mg, 84%). MS=412.3 (M+1), Rt=0.45 min [Method D].¹H NMR (400 MHz, METHANOL-d₄) ppm 8.83 (dd, J=4.3, 1.8 Hz, 1H), 8.71 (s,1H), 8.42 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.48 (dd, J=8.3, 4.3 Hz, 1H),4.43-4.57 (m, 1H), 4.16 (s, 3H), 3.11 (s, 3H), 1.81 (dd, J=12.6, 3.0 Hz,2H), 1.58 (t, J=12.4 Hz, 2H), 1.37 (s, 6H), 1.25 (s, 6H).

Example 32 Synthesis of6-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-7-ol

A mixture of5-(7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(30 mg, 0.073 mmol) and pyridine hydrochloride (126 mg, 1.093 mmol) washeated in a microwave at 160° C. for 30 minutes. The resulting solid wasdissolved into methanol and concentrated onto a mixture of silica gel(500 mg) and sodium bicarbonate (14.6 mmol, 122 mg) and subjected toflash column chromatography (4 g silica gel, 1-17% 1.4 N ammonia in MeOHgradient in DCM over 30 column volumes) to provide6-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-7-olas a yellow solid (24 mg, 83%). MS=398.3 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) ppm 8.67 (d, J=3.0 Hz, 1H), 8.49 (s, 1H), 8.29 (d, J=7.6Hz, 1H), 7.36 (s, 1H), 7.28 (dd, J=8.3, 4.3 Hz, 1H), 4.55 (t, J=12.1 Hz,1H), 3.13 (s, 3H), 1.90 (dd, J=12.6, 3.0 Hz, 2H), 1.62-1.78 (m, 2H),1.46 (s, 6H), 1.33 (s, 6H).

Synthesis of Intermediates Intermediate 7: Synthesis of2-bromo-5-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)-1,3,4-thiadiazole

LiHMDS (1M solution in TBME, 1.72 mL, 1.72 mmol) was added to a stirred,ice cooled suspension of 2,2,6,6-tetramethylpiperidin-4-ol (248 mg,1.578 mmol) in DMF (5 mL) under nitrogen atmosphere. The resultingsolution was stirred at 0° C. for 30 minutes then heated at 50° C. andfor 3 hours. The reaction mixture was quenched by addition of MeOH (5mL), acidified by addition of TFA, and loaded onto a 5 g SCX cartridge(pre-wet with MeOH). The cartridge was washed with MeOH (20 mL) thenflushed with 7M NH₃ in MeOH (15 mL). The combined basic flushes wereconcentrated in vacuo to afford the crude product as a light brownsolid. The crude material was pre-absorbed onto silica gel and purifiedby flash chromatography using a 12 g silica cartridge, running aMeOH/DCM gradient, to afford the title compound as a pale brown solid(227 mg, 49% yield). LC-MS Rt 0.72 min; MS m/z 322.1 [M+2]⁺ [Method A].¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.26-5.38 (m, 1H), 2.01-2.17 (m, 2H),1.42 (br. s., 1H) 1.23-1.32 (m, 2H), 1.17 (s, 6H), 1.10 (br. s., 6H).

Intermediate 8: Synthesis of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-1H-pyrazol-3-amine

Step 1: 1-(4-Bromo-3-methoxyphenyl)-1H-pyrazol-3-amine

A mixture of 1-bromo-4-iodo-2-methoxybenzene (2.5 g, 7.99 mmol),3-aminopyrazole (0.797 g, 9.59 mmol), salicylaldoxime (0.219 g, 1.598mmol), Cu₂O (91 mg, 0.479 mmol), and Cs₂CO₃ (3.9 g, 11.98 mmol) in DMF(8 mL) was degassed with N₂ and heated at 95° C. overnight. Aftercooling to RT, the mixture was filtered through celite and rinsed withEtOAc. The filtrate was washed with water and brine. The organicsolution was dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (10%˜60% EtOAc inHeptane) to give 1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-amine (800 mg,MS: 270.3 [M+H⁺]).

Step 2:N-(1-(4-Bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoroacetamide

To an ice cold solution of1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-amine (200 mg, 0.746 mmol) andpyridine (0.263 mL, 1.343 mmol) in DCM (5 mL) was added trifluoroaceticanhydride (0.124 mL, 0.895 mmol). The reaction mixture was stirred atroom temperature for 3 h. The reaction mixture was diluted with DCM,washed with aqueous 1N HCl solution, aqueous saturated NaHCO₃, thendried over Na₂SO₄, filtered and concentrated under reduced pressure togive 320 mg ofN-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoroacetamide,which was used in the next step without further purification.

Step 3:N-(1-(4-Bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoro-N-methylacetamide

To a mixture ofN-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoroacetamide(320 mg, 0.879 mmol) and K₂CO₃ (146 mg, 1.055 mmol) in DMF (2 mL) wasadded MeI (202 mg, 1.055 mmol). The reaction mixture was stirred at roomtemperature overnight. The reaction mixture was poured into water andextracted with Et₂O. The combined organic layers were washed with water,dried over Na₂SO₄, filtered and concentrated under reduced pressure togiveN-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoro-N-methylacetamide(300 mg, MS: 380.0 [M+H⁺]).

Step 4: 1-(4-Bromo-3-methoxyphenyl)-N-methyl-1H-pyrazol-3-amine

To an ice cold solution ofN-(1-(4-bromo-3-methoxyphenyl)-1H-pyrazol-3-yl)-2,2,2-trifluoro-N-methylacetamide(300 mg, 0.793 mmol) in EtOH (5 mL) was added a solution of 21% sodiumethoxide in EtOH (0.4 mL, 0.793 mmol). The mixture was stirred at roomtemperature overnight, then was poured into water. The mixture wasextracted with EtOAc. The combined organic layers were washed withaqueous saturated NaHCO₃ solution, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give1-(4-bromo-3-methoxyphenyl)-N-methyl-1H-pyrazol-3-amine (200 mg, MS:284.3 [M+H⁺]).

Step 5:1-(3-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-1H-pyrazol-3-amine

A degassed reaction mixture of1-(4-bromo-3-methoxyphenyl)-N-methyl-1H-pyrazol-3-amine (200 mg, 0.709mmol), bis(pinacolato)diboron (270 mg, 1.063 mmol), Pd(dppf)Cl₂ (51.9mg, 0.071 mmol), dppf (39.3, 0.071 mmol) and potassium acetate (451 mg,2.127 mmol) in 1,4-dioxane (5 mL) was heated at 90° C. overnight. Aftercooling to RT, the mixture was filtered through celite and washed withEtOAc. The filtrate was concentrated and the residue was purified bysilica gel chromatography (10%˜60% EtOAc in Heptane) to give1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-methyl-1H-pyrazol-3-amine(160 mg, MS: 330.2 [M+H⁺]).

Intermediate 9: Synthesis of6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one

To a 100 mL round bottom flask containing 1,4-dioxane (21 mL) was added5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-one (1.0 g, 4.15 mmol),bis(pinacolato)diboron (1.6 g, 6.22 mmol), and potassium acetate (1.3 g,13.3 mmol). The suspension was degassed with nitrogen for 5 min, then1,1′-bis(diphenylphosphino)ferrocene (0.23 g, 0.415 mmol) andPdCl₂(dppf) (0.30 g, 0.415 mmol) were added. The resulting suspensionwas heated at 80° C. for 18 h. The reaction was then cooled to roomtemperature, diluted with ethyl acetate, filtered through celite andconcentrated in vacuo. The crude product was purified by silica gelchromatography to afford6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-one(1.1 g) MS [M+H⁺]=289.4

Intermediate 10: Synthesis of7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carbonitrile

Step 1: 6-Chloro-7-methoxyquinoline

A solution of sulfuric acid (35 mL) in water (35 mL) was treated with3-nitrobenzenesulfonic acid (35.1 g, 159 mmol) and glycerol (80 ml, 1.1mol) to give a thick grey suspension. The suspension was heated to 75°C. and 4-chloro-3-methoxyaniline (25.0 g, 159 mmol) was added. Themixture was stirred at 140° C. for 1 h. Additional quantities of water(35 mL), sulfuric acid (35 mL) and glycerol (40 mL) were added and thereaction was stirred an additional 2 h at 140° C. The solution wascooled to room temperature, poured onto ice, and the pH was adjusted to13 by addition of concentrated ammonium hydroxide. The mixture wasextracted with EtOAc (3×) and the extracts were washed with brine, driedover Na₂SO₄ and concentrated. Following the general procedure forquinoline purification described by Leir, C. M. J. Org. Chem., 1977, 42,911, the residue was dissolved into 2 M HCl (500 mL) and zinc chloride(43.2 g, 317 mmol) was added, resulting in immediate formation of aprecipitate. The mixture was stirred for 30 min. The solids wereisolated by filtration, washing with cold 2 M HCl, 2-propanol, thenwater. The solids were added to concentrated ammonium hydroxide (400 mL)and the mixture was stirred for 10 min. EtOAc was added and the mixturewas stirred for 5 min. The mixture was extracted with EtOAc (3×) and theextracts were washed with brine, dried over Na₂SO₄ and concentrated to adark brown residue consisting of a mixture of the two possiblecyclization regioisomers. Silica gel chromatography (15-100% gradient ofEtOAc in DCM) provided 6-chloro-7-methoxyquinoline (7.03 g) as a beigesolid. MS (M+1)=194.1, ¹H NMR (400 MHz, Methanol-d 4) δ 8.78 (dd, J=4.5,1.6 Hz, 1H), 8.24 (dd, J=8.4, 1.4 Hz, 1H), 8.01 (s, 1H), 7.47 (s, 1H),7.43 (dd, J=8.3, 4.5 Hz, 1H), 4.06 (s, 3H).

Step 2: 6-Chloro-7-methyoxyquinoline 1-oxide

In a 100 mL round bottom flask, 6-chloro-7-methoxyquinoline wasdissolved in DCM (25.8 mL) and MTO (0.051 g, 0.207 mmol) was added. Thereaction mixture was capped and vented with a needle, then placed in anice bath to cool. Once cool, hydrogen peroxide (0.633 mL, 10.33 mmol)was added drop-wise. When the addition was complete, the reactionmixture was removed from cooling, warmed to room temperature and stirredovernight (18 h). MnO₂ (10 mg, 0.115 mmol) was added and the reactionmixture was stirred for an additional 2 h. The reaction mixture wasfiltered through celite, washing with DCM, then concentrated in vacuo toyield 6-chloro-7-methyoxyquinoline 1-oxide (1.036 g) MS [M+H⁺]=210.3.

Step 3: 6-Chloro-7-methoxyquinoline-2-carbonitrile

A 50 mL flask containing acetonitrile (6.0 mL) was charged with6-chloro-7-methoxyquinoline 1-oxide (0.25 g, 1.19 mmol), TEA (0.33 mL,2.39 mmol), and trimethylsilyl cyanide (0.48 mL, 3.58 mmol). Thereaction mixture was heated at 80° C. for 2 h, cooled to roomtemperature and concentrated in vacuo. The residue was basified usingsaturated Na₂CO₃ and the product was extracted with DCM. The organiclayer was dried with MgSO4, filtered and concentrated in vacuo to afford6-chloro-7-methoxyquinoline-2-carbonitrile (0.20 g) MS [M⁺]=219.4.

Step 4:7-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carbonitrile

To a 5 mL microwave vial containing 1,4-dioxane (2.5 mL) was added6-chloro-7-methoxyquinoline-2-carbonitrile (0.11 g, 0.503 mmol),bis(pinacolato)diboron (0.26 g, 1.01 mmol), and potassium acetate (0.30g, 3.02 mmol). The suspension was degassed with nitrogen for 5 min.PdCl₂(dppf) dichloromethane adduct (0.04 g, 0.05 mmol) was added and theresulting suspension was heated at 100° C. for 2 h. The reaction wascooled to room temperature, diluted with ethyl acetate, filtered throughcelite and concentrated in vacuo to afford the crude product,7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carbonitrileMS [M+H⁺]=311.2.

Synthesis of Examples

By employing similar methods as described for the preparation of Example1, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 33

386.2, 0.49 min, D (DMSO-d₆) δ ppm 8.27 (d, J = 8.08 Hz, 1H), 7.73 (d, J= 1.52 Hz, 1H), 7.54 (dd, J = 8.34, 1.26 Hz, 1H), 4.35-4.45 (m, 1H),4.01 (s, 3H), 3.00 (s, 3H), 1.61 (dd, J = 11.87, 3.28 Hz, 2H), 1.42 (t,J = 12.13 Hz, 2H), 1.28 (br. s., 1H), 1.21 (s, 6H), 1.08 (s, 6H)3-methoxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 34

374.2, 0.49 min, D (DMSO-d₆) δ ppm 8.27 (t, J = 7.58 Hz, 1H), 8.08 (dd,J = 11.12, 1.01 Hz, 1H), 7.82 (dd, J = 8.34, 1.26 Hz, 1H), 4.41 (br. s.,1H), 3.04 (s, 3H), 1.59- 1.70 (m, 2H), 1.50 (br. s., 2H), 1.24 (br. s.,6H), 1.12 (br. s., 6 H) 3-fluoro-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 35

407.2, 0.53 min, D (DMSO-d₆) δ ppm 8.26 (t, J = 7.83 Hz, 1H), 7.94-7.85(m, 2H), 4.29-4.39 (m, 1H), 3.89 (s, 3H), 3.04 (s, 3H), 1.63 (dd, J =11.87, 3.28 Hz, 2H), 1.44 (t, J = 12.13 Hz, 2H), 1.29 (s, 1H), 1.21 (s,6H), 1.09 (s, 6H) methyl 3-fluoro-4-(5- (methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2- yl)benzoate 36

456.3, 0.50 min, D (DMSO-d₆) δ ppm 8.32 (d, J = 2.53 Hz, 1H), 8.08 (d, J= 8.59 Hz, 1 H), 7.39-7.46 (m, 2H), 5.86 (d, J = 2.53 Hz, 1H), 5.63-5.68 (m, 1H), 4.30-4.38 (m, 1H), 3.99 (s, 3H), 2.98 (s, 3H), 2.77 (d, J= 5.56 Hz, 3H), 1.62 (d, J = 10.61 Hz, 2H), 1.43 (t, J = 11.12 Hz, 2H),1.22 (s, 6H), 1.10 (s, 6H) 5-(2-methoxy-4-(3-(methylamino)-1H-pyrazol-1- yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 37

437.2, 0.52 min, D (Chloroform-d) δ 8.84 (s, 1 H), 8.28 (d, J = 8.3 Hz,1H), 7.48- 7.65 (m, 2H), 4.47-4.65 (m, 1H), 4.13 (s, 3H), 3.09 (s, 3H),1.82 (dd, J = 12.2, 3.4 Hz, 2H), 1.32-1.45 (m, 8H), 1.20 (s, 6H)7-methoxy-6-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinoline-2-carbonitrile

By employing similar methods as described for the preparation of Example6, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 38

455.3, 0.48 min, D (DMSO-d₆) δ ppm 8.24 (d, J = 8.59 Hz, 1H), 7.82 (d, J= 7.58 Hz, 1H), 7.47-7.54 (m, 2H), 6.85 (d, J = 2.02 Hz, 1H), 6.68 (dd,J = 7.07, 2.02 Hz, 1H), 5.37-5.45 (m, 1 H), 4.08 (s, 3H), 3.47 (s, 3H),2.15 (d, J = 10.11 Hz, 2H), 1.31 (br. s., 2H), 1.21 (br. s., 6H), 1.12(br. s., 6H) 4-(3-methoxy-4-(5-((2,2,6,6- tetramethylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin- 2(1H)-one

By employing similar methods as described for the preparation of Example25, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt Example Compound Method 1H NMR 400 MHz 39

472.2 [M]⁺ 0.48 min, D (DMSO-d₆) δ ppm 8.13 (d, J = 8.59 Hz, 1H), 7.98(d, J = 2.02 Hz, 1H), 7.80-7.86 (m, 2H), 6.81 (d, J = 2.02 Hz, 1H), 6.66(dd, J = 7.33, 2.27 Hz, 1H), 4.42 (br. s., 1H), 3.46 (s, 3H), 3.03 (s,3H), 1.64 (br. s., 2H), 1.45 (br. s., 2H), 1.23 (br. s., 7H), 1.11 (br.s., 6H) 4-(3-chloro-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin- 2(1H)-one 40

431.2, 0.49 min, D (DMSO-d₆) δ ppm 8.23 (br. s., 2H), 7.99 (d, J = 8.08Hz, 1H), 7.90 (d, J = 1.52 Hz, 1H), 7.67- 7.78 (m, 1H), 4.29-4.44 (m,1H), 3.01 (s, 3H), 1.62 (dd, J = 12.13, 3.03 Hz, 2H), 1.43 (t, J = 12.13Hz, 2H), 1.21 (s, 6H), 1.09 (s, 6H) 5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 41

485.2 [M]⁺, 0.54 min, D (DMSO-d₆) δ ppm 8.01 (d, J = 8.08 Hz, 1H), 7.89(s, 1H), 7.66 (d, J = 1.52 Hz, 1H), 7.56 (dd, J = 8.34, 1.77 Hz, 1H),4.31- 4.44 (m, 1H), 4.11 (t, J = 6.06 Hz, 2H), 2.94-3.06 (m, 5H),1.96-2.04 (m, 2H), 1.81-1.90 (m, 2H), 1.62 (dd, J = 11.87, 3.28 Hz, 2H),1.43 (t, J = 12.38 Hz, 2H), 1.29 (br. s., 1H), 1.21 (s, 6H), 1.09 (s,6H) 5-(2-chloro-4-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl)-N- methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 42

412.2 0.46 min, D (DMSO-d₆) δ ppm 9.03 (d, J = 11.12 Hz, 1H), 8.85 (d, J= 2.02 Hz, 1H), 8.33 (s, 1H), 8.07-8.13 (m, 1H), 7.93-8.07 (m, 3H),4.44-4.55 (m, 1H), 3.90 (s, 3H), 3.07 (s, 3H), 1.87- 2.02 (m, 4H), 1.50(s, 6H), 1.45 (s, 6H) N-methyl-5-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2- amine. Hydrochloride salt 43

432.2, 0.54 min, A (DMSO-d₆) δ ppm 8.35 (s, 1 H), 8.02-8.07 (m, 2H),7.90 (d, J = 2.02 Hz, 1H), 7.70-7.74 (m, 1H), 5.42 (tt, J = 11.31, 4.11Hz, 1H), 3.88 (s, 3H), 2.16 (dd, J = 11.62, 4.04 Hz, 2H), 1.42 (br. s.,1H), 1.32 (t, J = 11.62 Hz, 2H), 1.20 (s, 6H), 1.11 (s, 6H)2-(2-chloro-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin- 4-yl)oxy)-1,3,4-thiadiazole 44

472.2 [M]⁺, 0.58 min, D (DMSO-d₆) δ ppm 8.62 (d, J = 2.02 Hz, 1H),8.09-8.17 (m, 2H), 7.96 (d, J = 1.52 Hz, 1H), 7.80 (dd, J = 8.34, 1.77Hz, 1H), 6.95 (d, J = 8.59 Hz, 1H), 4.35- 4.44 (m, 1H), 3.92 (s, 3H),3.02 (s, 3H), 1.63 (dd, J = 12.13, 3.03 Hz, 2H), 1.44 (t, J = 12.38 Hz,2H), 1.29 (br. s., 1H), 1.21 (s, 6H), 1.09 (s, 6H) 5-(2-chloro-4-(6-methoxypyridin-3-yl)phenyl)- N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 45

441.3, 0.40 min, D (DMSO-d₆) δ ppm 8.39 (d, J = 2.53 Hz, 1H), 8.07 (t, J= 8.34 Hz, 1H), 7.82 (dd, J = 8.59, 2.53 Hz, 1H), 7.57-7.69 (m, 2H),6.53 (d, J = 9.09 Hz, 1H), 6.26 (s, 2H), 4.30-4.39 (m, 1H), 3.01 (s,3H), 1.63 (d, J = 9.60 Hz, 2H), 1.44 (t, J = 11.62 Hz, 2H), 1.29 (br.s., 1H), 1.22 (s, 6H), 1.09 (s, 6H) 5-(4-(6-aminopyridin-3-yl)-2-fluorophenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 46

429.3, 0.52 min, D (DMSO-d₆) δ ppm 12.77 (br. s., 1H), 8.08 (t, J = 8.08Hz, 1H), 7.69-7.78 (m, 2H), 6.58 (br. s., 1H), 4.29-4.39 (m, 1H), 3.02(s, 3H), 2.28 (s, 3H), 1.63 (d, J = 12.13 Hz, 2H), 1.45 (t, J = 11.12Hz, 2H), 1.29 (br. s., 1H), 1.22 (br. s., 6H), 1.10 (br. s., 6H)5-(2-fluoro-4-(3-methyl-1H- pyrazol-5-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 47

415.2, 0.49 min, D (DMSO-d₆) δ ppm 13.10 (br. s., 1H), 8.11 (t, J = 8.08Hz, 1H), 7.74-7.89 (m, 3H), 6.88 (s, 1H), 4.34 (t, J = 12.13 Hz, 1H),3.02 (s, 3H), 1.63 (d, J = 9.09 Hz, 2H), 1.39-1.51 (m, 2H), 1.29 (br.s., 1H), 1.22 (s, 6H), 1.09 (s, 6H) 5-(2-fluoro-4-(1 H-pyrazol-5-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 48

433.3, 0.49 min, D (DMSO-d₆) δ ppm 13.29 (br. s., 1H), 8.26 (br. s.,1H), 8.12 (br. s., 1 H), 7.84 (td, J = 7.58, 1.52 Hz, 1H), 7.68-7.73 (m,1H), 4.35 (tt, J = 12.57, 3.35 Hz, 1H), 3.02 (s, 3H), 1.63 (dd, J =11.62, 3.03 Hz, 2H), 1.44 (t, J = 12.13 Hz, 2H), 1.29 (br. s., 1H), 1.21(s, 6H), 1.09 (s, 6H) 5-(2,3-difluoro-4-(1 H-pyrazol-4-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 49

433.2, 0.52 min, D (DMSO-d₆) δ ppm 13.32 (br. s., 1H), 7.90 (d, J = 3.54Hz, 3H), 6.75 (br. s., 1H), 4.30-4.39 (m, 1H), 3.03 (s, 3H), 1.63 (dd, J= 11.87, 3.28 Hz, 2H), 1.45 (t, J = 12.13 Hz, 2H), 1.29 (br. s., 1H),1.21 (s, 6H), 1.09 (s, 6H) 5-(2,3-difluoro-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 50

433.3, 0.49 min, D (DMSO-d₆) δ ppm 13.26 (br. s., 1H), 8.20 (br. s.,2H), 7.85-7.92 (m, 2H), 4.31-4.40 (m, 1H), 3.02 (s, 3H), 1.62 (dd, J =12.13, 3.03 Hz, 2H), 1.44 (t, J = 12.13 Hz, 2H), 1.29 (br. s., 1H), 1.21(s, 6H), 1.09 (s, 6H) 5-(2,5-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 51

433.2, 0.52 min, D (DMSO-d₆) δ ppm 13.32 (br. s., 1H), 7.82-7.99 (m,3H), 6.76 (br. s., 1H), 4.31-4.39 (m, 1H), 3.03 (s, 3H), 1.63 (dd, J =11.62, 3.03 Hz, 2H), 1.40-1.49 (m, 2H), 1.29 (br. s., 1H), 1.21 (s, 6H),1.09 (s, 6H) 5-(2,5-difluoro-4-(1H-pyrazol- 5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 52

433.3, 0.47 min, D (DMSO-d₆) δ ppm 13.16 (br. s., 1H ), 8.29 (br. s.,2H), 7.58-7.67 (m, 2H), 4.29-4.38 (m, 1H), 3.01 (s, 3H), 1.63 (dd, J =12.13, 3.03 Hz, 2H), 1.44 (t, J = 12.13 Hz, 2H), 1.29 (br. s., 1H), 1.20(s, 6H), 1.09 (s, 6H) (2,6-difluoro-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 53

375.2, 0.43 min, D (METHANOL-d₄) δ ppm 8.25 (s, 2H), 8.04 (dd, J =11.62, 6.06 Hz, 1H), 7.80 (dd, J = 11.87, 6.32 Hz, 1H), 3.91 (dd, J =10.36, 7.33 Hz, 2H), 3.60 (dd, J = 10.61, 3.03 Hz, 2H), 3.29-3.37 (m,2H), 3.19-3.28 (m, 2H), 3.00 (dd, J = 11.37, 2.78 Hz, 2H)2-(2,5-difluoro-4-(1H-pyrazol- 4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 54

449.1, 0.51 min, D (DMSO-d₆) δ ppm 13.27 (br. s., 1H), 8.22 (br. s.,2H), 8.06 (d, J = 7.07 Hz, 1H), 7.91 (d, J = 11.62 Hz, 1H), 4.39 (t, J =11.62 Hz, 1H), 3.02 (s, 3H), 1.64 (d, J = 10.11 Hz, 2H), 1.40- 1.56 (m,2H), 1.22 (s, 6H), 1.10 (s, 6H) 5-(2-chloro-5-fluoro-4-(1 H-pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 55

416.2, 0.45 min, D (DMSO-d₆) 6 ppm 13.22 (br. s., 1H), 8.80 (t, J = 1.77Hz, 1H), 8.32 (br. s., 2H), 8.16 (dd, J = 12.13, 1.52 Hz, 1H), 4.26-4.36 (m, 1H), 3.03 (s, 3H), 1.64 (dd, J = 12.13, 3.03 Hz, 2H), 1.45 (t,J = 12.13 Hz, 2H), 1.22 (s, 6H), 1.10 (s, 6H)5-(3-fluoro-5-(1H-pyrazol-4- yl)pyridin-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 56

458.2 [M⁺], 0.51 min, D (DMSO-d₆) δ ppm 8.37 (d, J = 5.05 Hz, 1H), 8.32(d, J = 1.52 Hz, 1H), 8.13-8.20 (m, 2H), 7.25 (d, J = 5.56 Hz, 1H), 6.80(s, 2H), 4.34-4.43 (m, 1H), 3.03 (s, 3H), 1.61-1.68 (m, 2H), 1.45 (t, J= 12.63 Hz, 2H), 1.22 (s, 6H), 1.10 (s, 6H)5-(4-(2-aminopyrimidin-4-yl)- 2-chlorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin- 4-yl)-1,3,4-thiadiazol-2-amine 57

458.2 [M]⁺, 0.47 min, D (DMSO-d₆) δ ppm 8.43 (d, J = 1.52 Hz, 1H),8.34-8.30 (m, 1H), 8.22 (d, J = 6.06 Hz, 1H), 8.15 (d, J = 8.08 Hz, 1H),7.05 (br. s., 2H), 6.42 (d, J = 5.56 Hz, 1H), 4.30-4.42 (m, 1H), 3.03(s, 3H), 1.64 (dd, J = 12.13, 3.03 Hz, 2H), 1.45 (t, J = 12.38 Hz, 2H),1.22 (s, 6H), 1.10 (s, 6H) 5-(5-(2-aminopyrimidin-4-yl)-2-chlorophenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 58

478.2 0.57 min, D (DMSO-d₆) δ ppm 7.98 (dd, J = 10.61, 6.06 Hz, 1H),7.62 (dd, J = 11.12, 6.06 Hz, 1H), 4.33-4.45 (m, 1H), 3.03 (s, 3H), 2.66(s, 3H), 2.33 (s, 3H), 1.63 (dd, J = 12.13, 3.03 Hz, 2H), 1.44 (t, J =12.13 Hz, 2H), 1.30 (br. s, 1H), 1.21 (s, 6H), 1.09 (s, 6H)5-(4-(2,4-dimethylthiazol-5- yl)-2,5-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine59

478.2, 0.56 min, D (METHANOL-d₄) δ ppm 7.88- 8.06 (m, 1H), 7.27-7.45 (m,1H), 4.47 (m, 1H), 3.11 (s, 3H), 2.72 (s, 3H), 2.32-2.42 (m, 3H), 1.79(dd, J = 12.63, 3.03 Hz, 2H), 1.58 (t, J = 12.38 Hz, 2H), 1.35 (s, 6H),1.24 (s, 6H) 5-(4-(2,4-dimethylthiazol-5- yl)-2,3-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine

By employing similar methods as described for the preparation of Example26, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 60

538.3, 0.53 min, D (CHLOROFORM-d) δ ppm 12.77 (br. s., 1H), 7.30 (d, J =7.07 Hz, 1H), 7.15 (d, J = 1.52 Hz, 1H), 6.98-7.02 (m, 1H), 6.74 (d, J =1.52 Hz, 1H), 6.33 (dd, J = 7.07, 2.02 Hz, 1H), 4.31 (br. s., 1H), 3.52(s, 3H), 3.05 (s, 3H), 1.76 (dd, J = 12.63, 3.03 Hz, 2H), 1.39 (br. s.,3H), 1.28 (s, 6H), 1.16 (br. s., 6H) 4-(3-hydroxy-4-(5- (methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2- yl)-5-(trifluoromethoxy)phenyl)-1- methylpyridin-2(1H)-one

Example 61 Synthesis of5-(2-fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Step 1: 5-(2-Fluoro-6-methoxyphenyl)-1,3,4-thiadiazol-2-amine

A stirred mixture of 2-fluoro-6-methoxybenzoic acid (2 g, 11.76 mmol)and hydrazinecarbothioamide (1.607 g, 17.63 mmol) was cooled undernitrogen atmosphere in an ice bath and POCl₃ (3.29 mL, 35.3 mmol) wasadded drop-wise. On completion of the addition, the reaction mixture wasstirred at 78° C. for 3 hours. The reaction mixture was cooled in an icebath and quenched by addition of ice water (˜50 mL) to give asolid/gum-like mass. This solid was sonicated for 1.5 hours and theresulting suspension was diluted with a further 50 mL of water thenslurried at room temperature for ˜16 hours. The solid was collected byvacuum filtration, rinsed with water, re-suspended in saturatedNaHCO_(3(aq)) (˜100 mL) and slurried for ˜30 minutes. The resultingsolid was collected by vacuum filtration, then rinsed with water toafford the crude product as an off-white solid. The crude material waspre-absorbed onto silica gel and purified by flash chromatography usinga 120 g silica cartridge with a 0-10% MeOH/DCM gradient as the eluent toafford the title compound as a pale yellow solid (1.265 g, 45% yield).LC-MS: Rt 0.77 min; MS m/z 226.1 [M+H]⁺ [Method A]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.48 (td, J=8.34, 6.57 Hz, 1H), 7.29 (s, 2H), 7.02 (d,J=8.08 Hz, 1H), 6.91-6.99 (m, 1H), 3.85 (s, 3H).

Step 2: 2-Bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole

5-(2-Fluoro-6-methoxyphenyl)-1,3,4-thiadiazol-2-amine (1.265 g, 5.62mmol) was added, portion-wise, to a stirred solution of CuBr₂ (1.505 g,6.74 mmol) and t-BuNO₂ (0.992 mL, 8.42 mmol) in MeCN (16 mL) undernitrogen and the reaction mixture was stirred at room temperature for˜18 hours. The reaction mixture was quenched by addition of saturatedNH₄Cl_((aq)) (˜40 mL) and extracted with EtOAc (100 mL). The organicphase was separated, dried over MgSO₄, and filtered. The filtrate wasconcentrated in vacuo to afford the title compound as a brown solid(1.401 g, 86% yield). LC-MS: Rt 1.15 min; MS m/z 289.0 [M]⁺; [Method A].¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.63 (td, J=8.46, 6.32 Hz, 1H), 7.15 (d,J=8.59 Hz, 1H), 7.03-7.10 (m, 1H), 3.96 (s, 3H).

Step 3:5-(2-Fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

A stirred solution of2-bromo-5-(2-fluoro-6-methoxyphenyl)-1,3,4-thiadiazole (335 mg, 1.159mmol) and N,2,2,6,6-pentamethylpiperidin-4-amine (197 mg, 1.159 mmol) inNMP (2.5 mL) was heated at 120° C. for ˜18 hours. The reaction mixturewas diluted with saturated NaHCO_(3(aq)) (30 mL), water (20 mL), andextracted with DCM (75 mL). The organic phase was separated, dried overMgSO₄ and filtered. The filtrate was concentrated in vacuo to afford thecrude product as a brown oil/liquid. The crude material was purified byUV directed preparative HPLC under acidic conditions (0.1% TFA),collecting at 298 nm. The product containing fractions were combined andloaded onto a 5 g SCX cartridge (pre-wet with MeOH). The cartridge waswashed with MeOH (30 mL) then flushed with 7M NH₃ in MeOH (20 mL). TheMeOH/NH₃ was removed in vacuo to afford the title compound as an orangeoil (121 mg, 28% yield). LC-MS: Rt 0.88 min; MS m/z 379.4 [M+H]⁺;[Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.49 (td, J=8.34, 6.57 Hz,1H), 7.03 (d, J=8.59 Hz, 1H), 6.97 (t, J=9.09 Hz, 1H), 4.26-4.36 (m,1H), 3.86 (s, 3H), 2.98 (s, 3H), 1.62 (dd, J=11.62, 2.53 Hz, 2H), 1.42(t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).

Step 4:5-(4-Bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Nitrogen was bubbled through a stirred solution of5-(2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(121 mg, 0.32 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (122 mg,0.48 mmol) in dioxane (2.5 mL) To this solution was added dtbpy (9 mg,0.032 mmol) and [Ir(COD)(OMe)]₂ (11 mg, 0.016 mmol). The resultingsolution was de-gassed by bubbling nitrogen through for a further 10minutes, then heated at 90° C. for ˜16 hours. The reaction mixture wasconcentrated in vacuo and the residue taken up in a 1:1 mixture ofMeOH:water (4 mL). CuBr₂ (168 mg, 0.754 mmol) was added and theresulting suspension heated at 80° C. for ˜18 hours. The reactionmixture was diluted with 28% NH₄OH_((aq)) (10 mL) and extracted with DCM(20 mL). The organic phase was separated and concentrated in vacuo toafford the crude product as a dark brown oil. The crude material waspurified by UV directed preparative HPLC under acidic conditions (0.1%formic acid), collecting at 314 nm. The product containing fractionswere combined and loaded onto a 2 g SCX cartridge (pre-wet with MeOH).The cartridge washed with MeOH (˜15 mL) then flushed with 7M NH₃ in MeOH(10 mL). The MeOH/NH₃ was removed in vacuo to afford a light brownoil/glass-like solid as a crude mixture containing the title compoundwhich was used without further purification. LC-MS: Rt 1.04 min; MS m/z459.3 [M+2H]⁺ [Method A].

Step 5:5-(2-Fluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Pd(Ph₃P)₄ (11 mg, 0.009 mmol) was added to a stirred suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (55 mg,0.282 mmol) and5-(4-bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(86 mg, 0.188 mmol) in dioxane (1.5 mL), followed by a solution ofNaHCO₃ (60 mg, 0.564 mmol) in water (0.375 mL). The reaction mixture waspurged with nitrogen, sealed, and heated at 120° C. under microwaveirradiation for 1 hour. The reaction mixture was diluted with DCM (20mL) and washed with saturated NaHCO_(3(aq)) (10 mL). The organic phasewas separated and SiliaMetS-DMT (0.61 mmol/g, 145 mg, 0.09 mmol) wasadded. The resulting suspension was stirred at room temperature for ˜2hours then filtered. The filtrate was concentrated in vacuo to affordthe crude product as a light brown oil. The crude material was purifiedby UV directed preparative HPLC under basic conditions (NH₄OH modified),collecting at 328 nm to afford the title compound as a white solid (26mg, 32% yield). LC-MS: Rt 0.76 min; MS m/z 445.5 [M+H]⁺ [Method A]. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 13.09 (br. s., 1H), 8.26 (br. s., 2H),7.23-7.31 (m, 2H), 4.27-4.37 (m, 1H), 3.93 (s, 3H), 2.98 (s, 3H), 1.62(dd, J=11.87, 3.28 Hz, 2H), 1.42 (t, J=12.13 Hz, 2H), 1.20 (s, 6H), 1.09(s, 6H).

By employing similar methods as described for the preparation of Example61, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 62

401.1, 0.40 min, D (CHLOROFORM-d) δ ppm 7.87 (s, 2H), 6.96 (d, J = 10.61Hz, 1H), 6.85 (s, 1H), 3.94 (s, 3H), 3.77 (dd, J = 10.11, 7.58 Hz, 2H),3.51 (dd, J = 10.61, 3.03 Hz, 2H), 3.08 (br. s., 2H), 2.67-2.78 (m, 2H),2.63 (dd, J = 9.09, 2.53 Hz, 2H), 2.40 (s, 3H)2-(2-fluoro-6-methoxy-4-(1 H- pyrazol-4-yl)phenyl)-5- ((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 63

463.2, 0.50 min, D (DMSO-d6) δ 13.30 (s, 1H), 8.24 (s, 2H), 7.29 (dd, J= 5.7, 2.0 Hz, 1H), 4.35 (tt, J = 12.5, 3.6 Hz, 1H), 3.95 (s, 3H), 3.00(s, 3H), 1.63 (dd, J = 11.9, 3.5 Hz, 2H), 1.44 (t, J = 12.1 Hz, 2H),1.21 (s, 6H), 1.09 (s, 6H) 5-(2,3-difluoro-6-methoxy-4-(1H-pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine

Example 64 Synthesis of6-methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

Step 1:6-Methoxy-2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

To a stirred suspension of 6-methoxy-3,4-dihydroisoquinolin-1(2H)-one(50 mg, 0.282 mmol) and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (132 mg, 0.395 mmol) in DMF (0.7 mL) under nitrogen wasadded K₂CO₃ (78 mg, 0.564 mmol) followed by CuI (32 mg, 0.169 mmol). Thereaction mixture was heated at 150° C. for ˜18 hours. A further 1.4 eqof5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(132 mg, 0.395 mmol) and 0.6 eq of CuI (32 mg, 0.169 mmol) were addedand stirring was continued at 150° C. for an additional 48 hours. Thereaction mixture was diluted with EtOAc (10 mL) and filtered throughcelite. The filtrate was concentrated in vacuo to afford the crudeproduct as a dark brown oil. The crude material was purified by UVdirected preparative HPLC under acidic conditions (formic acid modified)collecting at 312 nm. The product containing fractions were combined andloaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge waswashed with MeOH (˜20 mL) then flushed with 10% DCM in [7M NH₃ inMeOH](12 mL). The DCM/MeOH/NH₃ was removed in vacuo to afford the titlecompound as a pale yellow/brown glass-like solid (28 mg, 23% yield).LC-MS: Rt 0.91 min; MS m/z 430.5 [M+H]⁺ [Method A]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.88-7.97 (m, 1H), 6.96-7.03 (m, 2H), 4.35 (t, J=6.57 Hz,2H), 4.16 (tt, J=12.19, 3.22 Hz, 1H), 3.85 (s, 3H), 3.14 (t, J=6.57 Hz,2H), 2.91 (s, 3H), 1.58 (dd, J=12.13, 3.03 Hz, 2H), 1.42 (t, J=11.87 Hz,2H), 1.20 (s, 6H), 1.09 (s, 6H).

Example 65 Synthesis of5-(2-chloro-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Step 1:5-(2-Chloro-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

To a stirred suspension of (2-chloro-4-fluorophenyl)boronic acid (251mg, 1.44 mmol) and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4) (400 mg, 1.2 mmol) in dioxane (10 mL) under nitrogenwas added Pd(PPh₃)₄ (69 mg, 0.06 mmol) followed by a solution of Na₂CO₃(382 mg, 3.6 mmol) in water (2.5 mL). The reaction mixture was sealedand heated at 120° C. under microwave irradiation for 1 hour. Thereaction mixture was diluted with DCM (100 mL) and washed with saturatedNaHCO_(3(aq)) (40 mL). The organic phase was separated, dried overMgSO₄, and filtered. The filtrate was diluted with MeOH (10 mL) andSiliaMetS-DMT (0.61 mmol/g, 0.984 mg, 0.6 mmol) was added. The resultingsuspension was stirred at room temperature for ˜18 hours then filtered.The filtrate was concentrated in vacuo to afford the crude product as ayellow/orange oil. The crude material was purified by flashchromatography using a 24 g silica cartridge running a gradient from2-10% [2M NH₃ in MeOH]/DCM to afford the title compound as a pale yellowsolid (312 mg, 68% yield). LC-MS: Rt 0.97 min; MS m/z 383.4 [M+H]⁺[Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.03 (dd, J=8.84, 6.32 Hz,1H), 7.65 (dd, J=9.09, 2.53 Hz, 1H), 7.36-7.43 (m, 1H), 4.34 (tt,J=12.38, 3.28 Hz, 1H), 3.00 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H),1.43 (t, J=12.38 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.08 (s, 6H).

Step 2:5-(2-Chloro-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Cs₂CO₃ (128 mg, 0.392 mmol) was added to a stirred solution of5-(2-chloro-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(50 mg, 0.131 mmol) and 1H-pyrazole (13 mg, 0.196 mmol) in DMF (1.3 mL).The reaction mixture was stirred at room temperature for 4 days thenwarmed to 60° C. and stirred for an additional 18 hours. The reactionmixture was diluted with DCM (10 mL), filtered through celite, and theDCM was removed in vacuo to afford the crude product as a pale brownliquid. The crude material was purified by UV directed preparative HPLCunder acidic conditions (formic acid modified), collecting at 324 nm.The product containing fractions were combined and loaded onto a 1 g SCXcartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10mL) then flushed with 10% DCM in [7M NH₃ in MeOH](10 mL). TheDCM/MeOH/NH₃ was removed in vacuo to afford the title compound as aclear glass-like solid (37 mg, 66% yield). LC-MS: Rt 0.97 min; MS m/z431.5 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.67 (d, J=2.53Hz, 1H), 8.14 (dd, J=5.56, 3.03 Hz, 2H), 7.97-8.02 (m, 1H), 7.83 (d,J=1.52 Hz, 1H), 6.64-6.60 (m, 1H), 4.37 (tt, J=12.25, 3.16 Hz, 1H), 3.02(s, 3H), 1.63 (dd, J=12.13, 3.03 Hz, 2H), 1.45 (t, J=12.13 Hz, 2H), 1.21(s, 6H), 1.09 (s, 6H).

By employing similar methods as described for the preparation of Example65, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 66

432.2, 0.50 min, D (DMSO-d₆) δ ppm 8.99 (d, J = 1.52 Hz, 1H), 8.24-8.28(m, 2H), 8.08-8.11 (m, 1H), 8.04 (d, J = 1.52 Hz, 1H), 4.38 (tt, J =12.44, 2.97 Hz, 1H), 3.03 (s, 3H), 1.64 (dd, J = 11.87, 3.28 Hz, 2H),1.45 (t, J = 12.38 Hz, 2H), 1.29 (br. s., 1H), 1.21 (s, 6H), 1.09 (s,6H) 5-(2-chloro-4-(1H-1,2,3-triazol- 1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 67

432.2, 0.58 min, D (DMSO-d₆) δ ppm 8.22-8.27 (m, 3H), 8.20 (d, J = 2.53Hz, 1H), 8.13 (dd, J = 8.59, 2.02 Hz, 1H), 4.37 (tt, J = 12.44, 2.97 Hz,1H), 3.03 (s, 3H), 1.64 (dd, J = 12.13, 3.03 Hz, 2H), 1.44 (t, J = 12.13Hz, 2H), 1.29 (br. s., 1H), 1.21 (s, 6H), 1.09 (s, 6H)(2-chloro-4-(2H-1,2,3-triazol-2- yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 68

432.2, 0.51 min, D (DMSO-d₆) δ ppm 9.45 (s, 1 H), 8.32 (s, 1H),8.19-8.24 (m, 2H), 8.03-7.98 (m, 1H), 4.38 (tt, J = 12.25, 3.41 Hz, 1H),3.02 (s, 3H), 1.63 (dd, J = 12.13, 3.54 Hz, 2H), 1.44 (t, J = 12.13 Hz,2H), 1.30 (br. s., 1H), 1.21 (s, 6H), 1.09 (s, 6H)(2-chloro-4-(1H-1,2,4-triazol-1- yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 69

446.2 [M]⁺, 0.50 min, D (DMSO-d₆) δ ppm 8.29 (d, J = 3.03 Hz, 1H), 8.01(d, J = 8.59 Hz, 1H), 7.87 (d, J = 2.53 Hz, 1H), 7.71-7.77 (m, 1H), 5.83(d, J = 2.53 Hz, 1H), 5.29 (s, 2H), 4.29-4.38 (m, 1H), 3.00 (s, 3H),1.62 (dd, J = 11.87, 3.28 Hz, 2H), 1.43 (t, J = 12.38 Hz, 2H), 1.28 (s,1H), 1.20 (s, 6H), 1.09 (s, 6H) 5-(4-(3-amino-1H-pyrazol-1-yl)-2-chlorophenyl)-N-methyl- N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Example 70 Synthesis of2-(2-chloro-4-(1H-imidazol-1-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole

Step 1: 5-(2-Chloro-4-iodophenyl)-1,3,4-thiadiazol-2-amine

A stirred mixture of 2-chloro-4-iodobenzoic acid (2 g, 7.08 mmol) andhydrazinecarbothioamide (0.968 g, 10.62 mmol) was cooled under nitrogenin an ice bath. POCl₃ (1.98 mL, 21.24 mmol) was added drop-wise and thereaction mixture was heated at 78° C. for 3 hours. The reaction mixturewas cooled in an ice bath before quenching by addition of ice water (50mL). The resulting solid/cake was sonicated for 1 hour to give a freestirring suspension. This material was left to slurry at roomtemperature for ˜18 hours then filtered under vacuum and rinsed withwater to afford the crude product as a pale yellow/orange solid. Thesolid was re-suspended in saturated NaHCO_(3(aq)) (50 mL), slurried atroom temperature for 2 hours, then collected by vacuum filtration toafford the title compound as a pale yellow solid (2.05 g, 86% yield).LC-MS: Rt 1.20 min; MS m/z 337.8 [M]⁺ [Method A]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.01 (d, J=1.52 Hz, 1H), 7.76-7.82 (m, 2H), 7.50 (s, 2H).

Step 2: 2-Bromo-5-(2-chloro-4-iodophenyl)-1,3,4-thiadiazole

5-(2-Chloro-4-iodophenyl)-1,3,4-thiadiazol-2-amine (2.05 g, 6.07 mmol)was added portion-wise to a stirred solution of CuBr₂ (1.628 g, 7.92mmol) and t-BuNO₂ (1.07 mL, 9.11 mmol) in MeCN (15 mL) under nitrogen.The resulting mixture was stirred at room temperature for 18 hours. Thereaction mixture was quenched by addition of saturated NH₄Cl_((aq)) (75mL) and extracted with EtOAc (100 mL×2). The combined organic phaseswere concentrated in vacuo to afford the crude product as a pale brownsolid. The crude material was pre-absorbed onto silica gel and purifiedby flash chromatography using a 120 g silica cartridge running agradient from 0-20% EtOAc/heptane to afford the title compound as anoff-white solid (1.795 g, 73% yield). MS m/z 402.6 [M+H]⁺ ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.15-8.19 (m, 1H), 7.91-7.97 (m, 2H).

Step 3: 2-(2-Chloro-4-iodophenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole

A stirred solution of2-bromo-5-(2-chloro-4-iodophenyl)-1,3,4-thiadiazole (600 mg, 1.49 mmol)and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole (377 mg, 2.99 mmol)in NMP (4 mL) was heated at 120° C. for ˜18 hours. The reaction mixturewas cooled to room temperature then saturated NaHCO_(3(aq)) (30 mL) wasadded. The resulting suspension was left to slurry for 1 hour beforefiltering under vacuum to afford the title compound as a pale brownsolid which was used in the next step without further purification.LC-MS: Rt 1.06 min; MS m/z 446.8 [M]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.03 (s, 1H), 7.77-7.86 (m, 2H), 3.71 (t, J=8.84 Hz, 2H), 3.36 (br. s.,2H), 2.97 (br. s., 2H), 2.40-2.54 (m, 4H), 2.22 (s, 3H).

Step 4:2-(2-Chloro-4-(1H-imidazol-1-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole

DMF (0.75 mL) was added to a nitrogen flushed flask containing copper(I)iodide (13 mg, 0.067 mmol), 2-(2-pyridyl)benzimidazole (13 mg, 0.067mmol) and cesium carbonate (273 mg, 0.839 mmol). The resultingsuspension was heated at 60° C. for 1 hour. 1H-Imidazole (23 mg, 0.336mmol) and2-(2-chloro-4-iodophenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole(150 mg, 0.336 mmol) were added and the mixture was heated at 90° C. for˜18 hours. The reaction mixture was diluted with EtOAc (30 mL) andfiltered through celite. The filtrate was concentrated in vacuo toafford a green oil. The crude material was taken up in MeOH (30 mL) andSiliaMetS-DMT (0.61 mmol/g, 1.098 g, 0.67 mmol) was added. The resultingsuspension was stirred at room temperature for 72 hours then theSiliaMetS-DMT was removed by vacuum filtration and the filtrate wasconcentrated in vacuo to afford the crude product as a yellow oil. Thecrude material was purified by mass directed preparative HPLC underacidic conditions (TFA modified). The product containing fractions werecombined, loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and thecartridge washed with MeOH (10 mL) then flushed with 7M NH₃ in MeOH (10mL). The MeOH/NH₃ was removed in vacuo to afford the title compound as awhite solid (22 mg, 17% yield). LC-MS: Rt 0.52 min; MS m/z 387.0 [M+H]⁺[Method D]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (s, 1H), 8.15 (d,J=8.59 Hz, 1H), 8.06 (d, J=2.02 Hz, 1H), 7.91 (s, 1H), 7.83 (dd, J=8.59,2.53 Hz, 1H), 7.15 (s, 1H), 3.72 (dd, J=10.36, 8.34 Hz, 2H), 3.37 (dd,J=10.36, 2.78 Hz, 2H), 3.00 (br. s., 2H), 2.56 (br. s., 4H), 2.26 (s,3H).

By employing similar methods as described for the preparation of Example70, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method 1H NMR 400 MHz 71

431.1, 0.41 min, D (DMSO-d₆) δ ppm 8.44 (s, 1H), 8.13 (d, J = 8.59 Hz,1H), 8.06 (d, J = 2.02 Hz, 1H), 7.92 (s, 1H), 7.83 (dd, J = 8.59, 2.02Hz, 1H), 7.15 (s, 1H), 4.34-4.43 (m, 1H), 3.02 (s, 3H), 1.63 (dd, J =12.13, 3.03 Hz, 2H), 1.44 (t, J = 12.13 Hz, 2H), 1.21 (s, 6H), 1.09 (s,6H) 5-(2-chloro-4-(1H-imidazol-1- yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine 72

415.2, 0.40 min, D (DMSO-d₆) δ ppm 8.44 (s, 1H), 8.18 (t, J = 8.59 Hz,1H), 7.88- 7.96 (m, 2H), 7.72 (dd, J = 8.59, 2.02 Hz, 1H), 7.15 (s, 1H),4.32-4.41 (m, 1H), 3.02 (s, 3H), 1.63 (dd, J = 12.13, 3.03 Hz, 2H), 1.44(t, J = 12.13 Hz, 2H), 1.21 (s, 6H), 1.09 (s, 6H)5-(2-fluoro-4-(1H-imidazol-1- yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4- yl)-1,3,4-thiadiazol-2-amine

Example 73 Synthesis of5-(2-methoxy-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Step 1:5-(4-Chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Nitrogen was bubbled through a stirred solution of5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine[Intermediate 4](1 g, 3.00 mmol) and (4-chloro-2-methoxyphenyl)boronicacid (0.615 g, 3.30 mmol) in dioxane (20 mL). To this mixture was addedPd(PPh₃)₄ (0.173 g, 0.150 mmol) followed by a solution of Na₂CO₃ (0.954g, 9.00 mmol) in water (5 mL). The reaction was heated at 80° C. for 18hours. The reaction mixture was cooled to RT, diluted with EtOAc (150mL) and washed with water (100 mL). The organic phase was separated,dried over MgSO₄, and filtered. The filtrate was concentrated in vacuoto afford the crude product as a dark red/brown oil which solidified onstanding. The crude material was purified by flash chromatography usingan 80 g silica cartridge running a gradient of [2M NH₃ in MeOH]/DCM toafford the title compound as an off-white solid (1.051 g, 89% yield).LC-MS: Rt 1.04 min; MS m/z 395.2 [M+H]⁺ [Method A]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.09 (d, J=8.59 Hz, 1H), 7.32 (d, J=2.02 Hz, 1H), 7.15(dd, J=8.59, 2.02 Hz, 1H), 4.35 (tt, J=12.38, 3.54 Hz, 1H), 3.97 (s,3H), 2.98 (s, 3H), 1.60 (dd, J=11.87, 3.28 Hz, 2H), 1.41 (t, J=12.13 Hz,2H), 1.27 (s, 1H), 1.21 (s, 6H), 1.08 (s, 6H).

Step 2:5-(2-Methoxy-4-(1H-pyrazol-5-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

To a stirred suspension of (1H-pyrazol-5-yl)boronic acid (14 mg, 0.139mmol) and5-(4-chloro-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(50 mg, 0.127 mmol) in dioxane (1 mL) was added Pd(PPh₃)₄ (7 mg, 0.006mmol) followed by a solution of Na₂CO₃ (40 mg, 0.380 mmol) in water(0.25 mL). The reaction mixture was purged with nitrogen, sealed, andheated at 120° C. under microwave irradiation for 30 minutes, then againat 145° C. Additional catalyst and boronate were added and the mixturewas heated for an additional minutes under microwave irradiation at anincreased temperature of 160° C. The reaction mixture was diluted withDCM (20 mL), washed with saturated NaHCO_(3(aq)) (10 mL) and the organicphase was separated and concentrated in vacuo to afford the crudeproduct as an oily residue. The crude material was purified by massdirected preparative HPLC under basic conditions (NH₄OH midified) toafford the title compound as a white solid (12.5 mg, 23% yield). LC-MS:Rt 0.81 min; MS m/z 427.3 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δppm 12.99 (br. s., 1H), 8.12 (d, J=8.08 Hz, 1H), 7.82 (br. s., 1H), 7.60(s, 1H), 7.54 (d, J=6.06 Hz, 1H), 6.84 (d, J=2.02 Hz, 1H), 4.31-4.41 (m,1H), 4.01 (s, 3H), 2.99 (s, 3H), 1.61 (dd, J=12.13, 3.54 Hz, 2H), 1.42(t, J=12.13 Hz, 2H), 1.27 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H).

By employing similar methods as described for the preparation of Example73, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt Example Compound Method ¹H NMR 400 MHz 74

472.3, 0.55 min, D (DMSO-d₆) δ ppm 8.16 (d, J = 8.08 Hz, 1H), 7.20 (d, J= 2.02 Hz, 1 H), 7.16 (dd, J = 8.08, 1.52 Hz, 1 H), 4.33-4.42 (m, 1 H),3.99 (s, 3 H), 2.99 (s, 3 H), 2.64 (s, 3 H), 2.45 (s, 3 H), 1.61 (dd, J= 11.87, 3.28 Hz, 2 H), 1.42 (t, J = 12.13 Hz, 2 H), 1.28 (br. s., 1 H),1.22 (s, 6 H), 1.09 (s, 6 H) 5-(4-(2,4-dimethylthiazol-5-yl)-2-methoxyphenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 75

438.3, 0.48 min, D (DMSO-d₆) δ ppm 9.02 (d, J = 2.02 Hz, 1H), 8.61 (dd,J = 5.05, 1.52 Hz, 1H), 8.17-8.24 (m, 2H), 7.50-7.57 (m, 2H), 7.45-7.49(m, 1H), 4.39 (tt, J = 12.51, 3.41 Hz, 1H), 4.06 (s, 3H), 3.00 (s, 3H),1.62 (dd, J = 12.13, 3.03 Hz, 2H), 1.43 (t, J = 12.38 Hz, 2H), 1.28 (br.s., 1H), 1.22 (s, 6H), 1.09 (s, 6H) 5-(2-methoxy-4-(pyridin-3-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 76

415.3, 0.48 min, D (DMSO-d₆) δ ppm 13.09 (br. s., 1H), 8.34 (br. s.,1H), 8.11 (br. s., 1H), 8.04 (t, J = 8.08 Hz, 1H), 7.68 (dd, J = 12.88,1.26 Hz, 1H), 7.61 (dd, J = 8.08, 1.52 Hz, 1H), 4.29-4.38 (m, 1H), 3.01(s, 3H), 1.62 (dd, J = 12.13, 3.03 Hz, 2H), 1.43 (t, J = 12.13 Hz, 2H),1.28 (br. s., 1H), 1.21 (s, 6H), 1.09 (s, 6H)5-(2-fluoro-4-(1H-pyrazol-4- yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 77

468.3, 0.56 min, D (DMSO-d₆) δ ppm 8.26 (d, J = 5.05 Hz, 1H), 8.21 (d, J= 8.08 Hz, 1H), 7.55 (d, J = 1.52 Hz, 1H), 7.51 (dd, J = 8.08, 1.52 Hz,1H), 7.42 (dd, J = 5.56, 1.52 Hz, 1H ), 7.25 - 7.24 (m, 1H), 4.39 (tt, J= 12.51, 3.41 Hz, 1 H), 4.06 (s, 3 H), 3.91 (s, 3 H), 3.00 (s, 3 H),1.62 (dd, J = 12.13, 3.54 Hz, 2 H), 1.42 (t, J = 12.13 Hz, 2 H), 1.28(br. s., 1 H), 1.22 (s, 6 H), 1.09 (s, 6 H) 5-(2-methoxy-4-(2-methoxypyridin-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine 78

468.3, 0.56 min, D (DMSO-d₆) δ ppm 8.62 (d, J = 2.02 Hz, 1H), 8.12-8.19(m, 2H), 7.46 (d, J = 1.52 Hz, 1H), 7.40 (dd, J = 8.08, 1.52 Hz, 1H),6.94 (d, J = 8.59 Hz, 1H), 4.39 (tt, J = 12.32, 3.09 Hz, 1H), 4.04 (s,3H), 3.92 (s, 3H), 2.99 (s, 3H), 1.62 (dd, J = 11.87, 3.28 Hz, 2H), 1.42(t, J = 12.13 Hz, 2H), 1.28 (br. s., 1H), 1.22 (s, 6H), 1.09 (s, 6H)5-(2-methoxy-4-(6- methoxypyridin-3-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4- thiadiazol-2-amine

Example 79 Synthesis of2-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole

Step 1: 5-(4-Bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine

To an ice cooled mixture of 4-bromo-2-chlorobenzoic acid (2 g, 8.49mmol) and hydrazinecarbothioamide (1.161 g, 12.74 mmol) was addedphosphorous oxychloride (2.375 mL, 25.5 mmol) slowly, and the reactionwas heated at 78° C. for 3 hours. After cooling to 0° C., ice water wasadded and the mixture was vigorously stirred for 1 hour. The resultingprecipitate was filtered, washed with water then re-suspended insaturated NaHCO_(3(aq)) and water (1:1) and stirred for 1 hour. Thesolid was filtered, washed with water, and dried in vacuo to afford thetitle compound which was used without further purification (2 g, 81%yield). MS m/z 291.9 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.80-8.09(m, 2H), 7.68 (dd, J=2.02, 8.59 Hz, 1H), 7.55 (br. s, 2H).

Step 2:5-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine

To a stirred solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(197 mg, 0.946 mmol) and5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (250 mg, 0.860 mmol)in dioxane (8 mL) was added Pd(PPh₃)₄ (50 mg, 0.043 mmol) followed by asolution of Na₂CO₃ (274 mg, 2.58 mmol) in water (2 mL). The reactionmixture was purged with nitrogen, sealed, and heated at 80° C. for 1hour under microwave irradiation, then for an additional 2.5 hours at anincreased temperature of 120° C. The reaction mixture was diluted withDCM (40 mL) and washed with saturated NaHCO_(3(aq)) (40 mL). A few mLsof saturated NaCl_((aq)) were added to clear the resulting slightemulsion and the organic phase separated, dried over MgSO₄, andfiltered. The filtrate was concentrated in vacuo to afford the crudeproduct as a yellow solid. The crude material was pre-absorbed ontosilica gel and purified by flash chromatography using a 24 g silicacartridge running a MeOH/DCM gradient to afford the title compound as apale yellow solid (118 mg, 47% yield). LC-MS: Rt 0.83 min; MS m/z 292.0[M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.31 (s, 1H),7.97-8.03 (m, 2H), 7.83 (d, J=1.52 Hz, 1H), 7.65 (dd, J=8.34, 1.77 Hz,1H), 7.41 (s, 2H), 3.87 (s, 3H).

Step 3:2-Bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole

5-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine(118 mg, 0.404 mmol) was added, portion-wise, to a stirred solution ofCuBr₂ (108 mg, 0.485 mmol) and t-BuNO₂ (0.071 mL, 0.607 mmol) in MeCN (1mL) under nitrogen atmosphere. On completion of the addition, thereaction was stirred at room temperature for 18 hours then quenched byaddition of saturated NH₄Cl_((aq)) (20 mL), and EtOAc (10 mL) was added.The resulting bi-phasic suspension was filtered under vacuum, rinsedwith water (10 mL), then EtOAc (10 mL). The filtrate was separated andthe organic phase dried over MgSO₄, filtered, and re-combined with thesolid from the first filtration. The solvent was removed in vacuo toafford the crude product as a light brown solid. The crude material waspre-absorbed onto silica gel and purified by flash chromatography usinga 12 g silica cartridge running a EtOAc/heptane gradient to afford thetitle compound as a white solid 70.5 mg, 49% yield). MS m/z 356.8 [M+H]+

Step 4:2-(2-Chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole

A stirred suspension of2-bromo-5-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole(70 mg, 0.197 mmol) and (3aR,6aS)-2-methyloctahydropyrrolo[3,4-c]pyrrole(75 mg, 0.590 mmol) in NMP (0.5 mL) was heated to 120° C. and theresulting solution was stirred for 16 hours. The reaction mixture wasdiluted with DCM (20 mL) and washed with saturated NaHCO_(3(aq)) (20mL). The organic phase was separated and the aqueous phase wasre-extracted with DCM (20 mL). The combined organic phases wereconcentrated in vacuo to afford the crude product as a dark brown oilyresidue. The crude material was purified by mass directed preparativeHPLC under acidic conditions (TFA modified) and the product containingfractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). Thecartridge was washed with MeOH (15 mL) then flushed with 7M NH₃ in MeOH(10 mL). The MeOH/NH₃ was removed in vacuo to afford the title compoundas a light brown solid (10 mg, 13% yield). LC-MS: Rt 0.79 min; MS m/z401.4 [M+H]⁺ [Method D]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.32 (s, 1H),7.99-8.03 (m, 2H), 7.84 (d, J=2.02 Hz, 1H), 7.65-7.69 (m, 1H), 3.88 (s,3H), 3.70 (dd, J=10.61, 8.08 Hz, 2H), 3.36 (dd, J=10.61, 3.03 Hz, 2H),2.99 (br. s., 2H), 2.55 (br. s., 4H), 2.25 (s, 3H). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 8.21 (d, J=8.08 Hz, 1H), 7.81 (s, 1H), 7.69 (s, 1H),7.57 (d, J=2.02 Hz, 1H), 7.46 (dd, J=8.34, 1.77 Hz, 1H), 3.99 (s, 3H),3.79 (dd, J=9.85, 7.83 Hz, 2H), 3.53 (d, J=11.12 Hz, 2H), 3.12 (br. s.,2H), 2.76 (br. s., 2H), 2.58 (d, J=8.08 Hz, 2H), 2.41 (br. s., 3H).

By employing similar methods as described for the preparation of Example79, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt Example Compound Method ¹H NMR 400 MHz 80

387.2, 0.41 min, D (METHANOL-d₄) δ ppm 7.99 (br. s., 2H), 7.92 (d, J =8.59 Hz, 1H), 7.71 (s, 1H), 7.56 (d, J = 8.59 Hz, 1H), 3.60-3.70 (m,2H), 3.32-3.43 (m, 2H), 3.03 (br. s., 2H), 2.62-2.73 (m, 2H), 2.47 (dd,J = 9.60, 3.03 Hz, 2H), 2.26 (s, 3H) 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 81

387.1, 0.41 min, D (METHANOL-d₄) δ ppm 8.00 (br. s., 2H), 7.93 (d, J =8.08 Hz, 1H), 7.71 (d, J = 2.02 Hz, 1H), 7.57 (dd, J = 8.34, 1.77 Hz,1H), 3.57-3.70 (m, 2 H), 3.47-3.55 (m, 1H), 3.32-3.41 (m, 1H), 2.96-3.08(m, 3H), 2.28-2.37 (m, 4H), 2.07-2.18 (m, 1H), 1.59-1.72 (m, 1H)2-(2-chloro-4-(1H-pyrazol-4- yl)phenyl)-5-((3aR,6aR)-1-methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-1,3,4- thiadiazole 82

405.1, 0.44 min, D (METHANOL-d₄) ppm 8.00 (br. s., 2H), 7.92 (d, J =8.08 Hz, 1H), 7.71 (d, J = 1.52 Hz, 1H), 7.57 (dd, J = 8.08, 1.52 Hz,1H), 3.93 (dd, J = 11.12, 3.03 Hz, 1H), 3.62-3.82 (m, 4H), 3.23- 3.31(m, 1H), 2.86-2.98 (m, 1H), 2.45 (dd, J = 13.14, 7.58 Hz, 1H), 2.34 (dd,J = 13.14, 3.54 Hz, 1H), 2.22 (s, 6H) 1-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2- yl)morpholin-2-yl)-N,N-dimethylmethanamine 83

415.1, 0.47 min, D (METHANOL-d₄) δ ppm 7.95- 8.07 (m, 2H) 7.87-7.94 (m,1H) 7.70 (d, J = 1.52 Hz, 1H) 7.56 3.57 (m, 2H) 3.30-3.42 (m, 2H)2.62-2.73 (m, 1H) 2.45- 2.58 (m, 2H) 2.28 (s, 3H) 1.53- 1.75 (m, 6H)1.18 (s, 1H) 2-(2-chloro-4-(1H-pyrazol-4- yl)phenyl)-5-(2-methyl-2,7-diazaspiro[4.5]decan-7-yl)- 1,3,4-thiadiazole 84

371.1, 0.40 min, D (METHANOL-d₄) δ ppm 7.94- 8.08 (m, 3H) 7.32-7.53 (m,2H) 3.65 (dd, J = 10.36, 8.34 Hz, 2H) 3.39 (dd, J = 10.61, 3.03 Hz, 2H)3.04 (br. s., 2H) 2.68 (dd, J = 9.60, 7.07 Hz, 2H) 2.47 (dd, J = 9.85,3.28 Hz, 2H) 2.26 (s, 3H) 2-(2-fluoro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-5- methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole

Example 85 Synthesis of2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole

Step 1: 5-(4-Iodo-2-methoxyphenyl)-1,3,4-thiadiazol-2-amine

To an ice cooled mixture of 4-iodo-2-methoxybenzoic acid (6.178 g, 22.22mmol) and hydrazinecarbothioamide (2.43 g, 26.7 mmol) was addedphosphorous oxychloride (6.21 mL, 66.7 mmol) slowly. The mixture washeated at 78° C. overnight. After cooling to 0° C., ice water was addedand the mixture was vigorously stirred for 1 hour. The resultingprecipitate was filtered, washed with water, and re-suspended insaturated NaHCO_(3(aq)) and water (1:1) for 1 hour. The solid wasfiltered, washed with water, and dried in vacuo to afford the crudecompound. The crude material was purified by flash chromatography(MeOH/CH2Cl2) to afford the title compound (1.2 g, 16% yield). MS m/z334.0 [M+H]⁺.

Step 2:5-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine

To a stirred suspension of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(137 mg, 0.660 mmol) and5-(4-iodo-2-methoxyphenyl)-1,3,4-thiadiazol-2-amine (200 mg, 0.6 mmol)in dioxane (4 mL) was added Pd(PPh₃)₄ (35 mg, 0.03 mmol) followed by asolution of Na₂CO₃ (191 mg, 1.801 mmol) in water (1 mL). The reactionwas purged with nitrogen then heated at 80° C. for 18 hours. Thereaction mixture was diluted with MeOH (20 mL), filtered through celite,and rinsed with DCM (20 mL). The filtrate was concentrated in vacuo toafford the crude product as an orange oily residue. The crude productwas pre-absorbed onto silica gel and purified by flash chromatographyusing a 24 g silica cartridge, running a MeOH/DCM gradient to afford thetitle compound as a pale yellow solid (107 mg, 62% yield). LC-MS: Rt0.81 min; MS m/z 288.1 [M+H]+[Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.27 (s, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.98 (s, 1H), 7.36 (d, J=1.52 Hz,1H), 7.28 (dd, J=8.08, 1.52 Hz, 1H), 7.13 (s, 2H), 3.99 (s, 3H), 3.88(s, 3H).

Step 3:2-Bromo-5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole

5-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine(205 mg, 0.713 mmol) was added portion-wise to a stirred solution ofCuBr₂ (191 mg, 0.865 mmol) and t-BuNO₂ (0.126 mL, 1.07 mmol) in MeCN (16mL) under nitrogen atmosphere. On completion of the addition, thereaction mixture was stirred at room temperature for 18 hours thenquenched by addition of saturated NH₄Cl_((aq)) (25 mL), diluted withwater (25 mL), and extracted with EtOAc (100 mL×2) then DCM (100 mL).The combined organic phases were dried over MgSO₄, filtered, and thefiltrate was concentrated in vacuo to afford the crude product as alight brown/orange solid. The crude material was pre-absorbed ontosilica gel and purified by flash chromatography using a 12 g silicacartridge, running a MeOH/DCM to afford the title compound as a lightyellow solid (80 mg, 32% yield). LC-MS: Rt 1.19 min; MS m/z 353.1 [M+2]⁺[Method A]. ¹H NMR (400 MHz, DMSO-d₆) ppm 8.36 (s, 1H), 8.25 (d, J=8.59Hz, 1H), 8.06 (s, 1H), 7.48 (d, J=1.52 Hz, 1H), 7.39 (dd, J=8.08, 1.52Hz, 1H), 4.09 (s, 3H), 3.89 (s, 3H).

Step 4:2-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole

DIPEA (116 μL, 0.666 mmol) was added to a stirred suspension of2-bromo-5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole(78 mg, 0.222 mmol) and tert-butyl2,6-diazaspiro[3.5]nonane-6-carboxylate (acetic acid salt, 127 mg, 0.444mmol) in NMP (444 μL) and the mixture was heated at 120° C. for 3 hours.The reaction mixture was diluted with DCM (10 mL), washed with saturatedNaHCO_(3(aq)) (10 mL), and the organic phase was separated. TFA (342 μL,4.44 mmol) was added and the resulting solution was stirred at roomtemperature for 18 hours. A further 1 mL TFA was added and the reactionmixture was warmed to 35° C. and stirred for 48 hours. The reactionmixture was loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and thecartridge was washed with MeOH (10 mL) then flushed with 7M NH₃ in MeOH(10 mL). The MeOH/NH₃ was removed in vacuo to afford the crude productas a brown oil. The crude material was purified by UV directedpreparative HPLC under acidic conditions (TFA modified) and the productcontaining fractions were loaded onto a 1 g SCX cartridge (pre-wet withMeOH). The cartridge was washed with MeOH (10 mL) and flushed with 7MNH₃ in MeOH (10 mL). The MeOH/NH₃ was removed in vacuo to afford thetitle compound a white foam-like solid (40.5 mg, 46% yield). LC-MS: Rt0.83 min; MS m/z 397.1 [M+H]⁺ [Method D], ¹H NMR (400 MHz, DMSO-d₆) ppm8.27 (s, 1H), 8.06 (d, J=8.08 Hz, 1H), 7.99 (s, 1H), 7.37 (d, J=1.52 Hz,1H), 7.29 (dd, J=8.08, 1.52 Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.81(d, J=7.58 Hz, 2H), 3.74 (d, J=7.58 Hz, 2H), 2.82 (s, 2H), 2.60 (t,J=5.05 Hz, 2H), 1.73 (t, J=5.56 Hz, 2H), 1.41 (quin, J=5.56 Hz, 2H).

By employing similar methods as described for the preparation of Example85, using appropriate starting materials, the following compound wasprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 86

397.2, 0.44 min, D (DMSO-d₆) δ ppm 8.27 (s, 1H), 8.07 (d, J = 8.08 Hz,1H), 7.99 (s, 1H), 7.37 (d, J = 1.52 Hz, 1H), 7.29 (dd, J = 8.08, 1.52Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3 H), 3.81 (s, 4H), 2.57-2.66 (m, 4H),1.62-1.71 (m, 4H) 2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,7- diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole

Example 87 Synthesis of2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-1-yl)phenol

To a solution of5-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Example 1) (30 mg, 0.070 mmol) in DCM (1.5 mL) was added BBr₃ (1Msolution in heptane, 0.352 mL, 0.352 mmol). The resulting bright yellowsuspension was stirred at room temperature for 2 h. The reaction mixturewas quenched by addition of MeOH (5 mL) and the resulting solution wasloaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge waswashed with MeOH (10 mL) then flushed with 7M NH₃ in MeOH (15 mL). Thesolvent was evaporated in vacuo. The resulting crude material wassonicated in MeOH (2 mL) and the resulting suspension was filtered undervacuum to afford the title compound as a pale yellow solid (14.9 mg,51.4% yield). LC-MS: Rt 0.55 min; MS m/z 413.3 [M+H]⁺ [Method D]. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.47 (d, J=2.02 Hz, 1H), 7.99 (d, J=8.59 Hz,1H), 7.73-7.78 (m, 1H), 7.47 (d, J=1.52 Hz, 1H), 7.36 (d, J=8.59 Hz,1H), 6.53-6.58 (m, 1H), 4.33 (t, J=12.13 Hz, 1H), 2.99 (s, 3H),1.58-1.69 (m, 2H), 1.47 (t, J=12.13 Hz, 2H), 1.23 (s, 6H), 1.12 (s, 6H).

By employing similar methods as described for the preparation of Example87, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 88

458.2 [M]⁺, 0.48 min, D (DMSO-d₆) δ ppm 8.03 (d, J = 8.59 Hz, 1H),7.91-7.96 (m, 2H), 7.86 (d, J = 2.02 Hz, 1H), 7.70 (dd, J = 8.34, 1.77Hz, 1H), 6.45 (d, J = 10.11 Hz, 1H), 4.34- 4.42 (m, 1H), 3.01 (s, 3H),1.61-1.67 (m, 2 H), 1.46 (t, J = 11.87 Hz, 2H), 1.22 (s, 6H), 1.10 (s,6H) 5-(3-chloro-4-(5-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2(1H)-one 89

442.2, 0.49 min, D (DMSO-d₆) δ ppm 8.16 (d, J = 2.53 Hz, 1H), 7.87 (d, J= 8.59 Hz, 1H), 7.33 (d, J = 2.02 Hz, 1H), 7.22 (dd, J = 8.84, 1.77 Hz,1H), 5.81 (d, J = 2.53 Hz, 1H), 5.62 (q, J = 4.55 Hz, 1H), 4.24-4.36 (m,1H), 2.98 (s, 3H), 2.75 (d, J = 5.05 Hz, 3H), 1.58-1.67 (m, 2H), 1.44(t, J = 12.13 Hz, 2H), 1.22 (s, 6H), 1.10 (s, 6H) 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2-yl)-5-(3-(methylamino)-1H- pyrazol-1-yl)phenol 90

431.2, 0.50 min, D (DMSO-d₆) δ ppm 13.08 (br. s., 1H), 8.19 (br. s.,2H), 7.12- 7.26 (m, 2H), 4.29-4.41 (m, 1H), 3.02 (s, 3H), 1.64 (dd, J =12.13, 3.03 Hz, 2H), 1.46 (t, J = 12.13 Hz, 2H), 1.22 (s, 6H), 1.10 (s,6H) 3-fluoro-2-(5-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4-yl)phenol 91

449.2, 0.52 min, D (DMSO-d₆) δ 13.26 (s, 1H), 8.14 (s, 2H), 7.15 (d, J =6.1 Hz, 1 H), 4.45-4.28 (m, 1 H), 3.03 (s, 3H), 1.65 (dd, J = 12.1, 3.5Hz, 2H), 1.48 (t, J = 12.2 Hz, 2H), 1.23 (s, 6H), 1.11 (s, 6H)3,4-difluoro-2-(5-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4-yl)phenol

By employing similar methods as described for the preparation of Example1 and Example 87, using appropriate starting materials, the followingcompound was prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 92

401.2, 0.48 min, D ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.58 (m, 12H)1.81-1.93 (m, 2H) 1.95-2.10 (m, 2H) 2.66 (dd, J = 6.53, 5.02 Hz, 2H)2.97-3.12 (m, 5H) 4.35-4.70 (m, 1 H) 7.20 (s, 1H) 8.12 (d, J = 12.05 Hz,1 H) 8.20 (s, 1H) 9.17 (d, J = 11.80 Hz, 1H) 11.34 (br. s., 1H)6-hydroxy-5-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-2,3-dihydro-1H-inden-1- one

By employing similar methods as described for the preparation of Example25 and Example 87, using appropriate starting materials, the followingcompound was prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 93

413.2, 0.50 min, D (DMSO-d₆) δ ppm 13.01 (br. s., 1H), 8.09 (br. s.,2H), 7.80 (d, J = 1.00 Hz, 1H), 7.04-7.33 (m, 2H), 4.12-4.45 (m, 1H),2.99 (s, 3H), 1.62 (dd, J = 3.28, 11.87 Hz, 2H), 1.43 (t, J = 12.13 Hz,2H), 1.19 (s, 6H), 1.09 (s, 6H) 2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4- yl)amino)-1,3,4-thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol

By employing similar methods as described for the preparation of Example85 and Example 87, using appropriate starting materials, the followingcompounds were prepared:

LCMS M + 1, Rt Example Compound Method ¹H NMR 400 MHz 94

383.1, 0.45 min, D (DMSO-d₆) δ ppm 10.90 (br. s., 1H), 8.06 (s, 1H),7.72-7.80 (m, 2H), 7.03-7.10 (m, 2H), 3.78-3.87 (m, 7H), 2.94 (s, 1H),2.56-2.72 (m, 2H), 2.29- 2.45 (m, 2H), 1.67 (br. s., 2H), 1.51 (br. s.,2H) 2-(5-(2,6- diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)phenol 95

383.1, 0.44 min, D (DMSO-d₆) δ ppm 8.12 (s, 1H), 7.86 (d, J = 8.08 Hz,1H), 7.82 (s, 1H), 7.15-7.09 (m, 2H), 3.87 (s, 3H), 3.82 (s, 4H), 2.67(t, J = 4.80 Hz, 4H), 1.65- 1.75 (m, 4H) 2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-5- (1-methyl-1H-pyrazol-4- yl)phenol

By employing similar methods as described for the preparation of Example61 and Example 87, using appropriate starting materials, the followingcompounds were prepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 96

373.2, 0.43 min, D (DMSO-d₆) δ ppm 9.26 (br. s., 2H), 8.20 (s, 2H), 7.23(dd, J = 12.63, 1.52 Hz, 1H), 7.18 (s, 1 H), 3.78-3.70 (m, 2H), 3.57-3.59 (m, 4H), 3.43 (dd, J = 10.61, 6.06 Hz, 2H), 3.13-3.27 (m, H)3-fluoro-2-(5-((3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4- thiadiazol-2-yl)-5-(1H-pyrazol-4-yl)phenol•Di- hydrochloride salt 97

477.2, 0.63 min, D (DMSO-d₆) δ ppm 13.09 (br. s., 1H), 8.31 (br. s.,1H), 8.04 (br. s., 1H), 7.38 (d, J = 1.52 Hz, 1H), 7.21 (d, J = 2.02 Hz,1H), 4.29- 4.39 (m, 1 H), 3.02 (s, 3H), 1.64 (dd, J = 11.87, 3.28 Hz,2H), 1.46 (t, J = 12.38 Hz, 2H), 1.22 (s, 6H), 1.10 (s, 6H)3-chloro-2-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4-yl)phenol

Example 98 Synthesis of2-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole

Step 1:5-((2,2,6,6-Tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazol-2-amine

A stirred mixture of 2-(2,2,6,6-tetramethylpiperidin-4-yl)acetic acid(410 mg, 2.057 mmol) and hydrazinecarbothioamide (281 mg, 3.09 mmol) wascooled under nitrogen in an ice bath.

POCl₃ (0.575 mL, 6.17 mmol) was added drop-wise and the mixture washeated at 78° C. for 3 hours. The reaction mixture was cooled in an icebath and quenched by addition of ice water (20 mL). The resultingmixture was sonicated for 20 minutes and the resulting suspension wasstirred at room temperature for 72 hours. The resulting solution wasbasified by addition of NaOH (pellets added portion-wise over ˜15minutes). The resulting suspension was stirred at room temperature for 1hour before filtering under vacuum and rinsing with water to afford thetitle compound as a pale brown solid (118 mg, 22% yield). LC-MS: Rt 0.44min; MS m/z 255.3 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm6.98 (s, 2H), 2.66 (d, J=7.07 Hz, 2H), 2.03 (br. s., 1H), 1.49 (d,J=10.61 Hz, 2H), 1.08 (s, 6H), 0.99 (br. s., 6H), 0.78 (t, J=12.13 Hz,2H).

Step 2:2-Bromo-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole

5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazol-2-amine(117 mg, 0.46 mmol) was added portionwise to a stirred solution of CuBr₂(123 mg, 0.552 mmol) and t-BuNO₂ (0.081 mL, 0.69 mmol) in MeCN (1 mL)under nitrogen atmosphere. On completion of the addition, the reactionmixture was stirred at room temperature for 18 hours then a further 1.5eq of t-BuNO₂ (0.081 mL, 0.69 mmol) was added. The reaction mixture wasstirred at room temperature for 10 minutes, and a further 1.2 eq ofCuBr₂ (123 mg, 0.552 mmol) was added. The reaction mixture was stirredat room temperature for a further 18 hours, then quenched by addition ofsaturated NH₄Cl_((aq)) (10 mL) and extracted with DCM (20 mL). Theorganic phase was separated and concentrated in vacuo to afford thecrude product as a brown oil. The crude material was purified by UVdirected preparative HPLC under acidic conditions (formic acid modified)and the product containing fractions were loaded onto a 1 g SCXcartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10mL) then flushed with 7M NH₃ in MeOH (10 mL). The MeOH/NH₃ was removedin vacuo to afford the title compound as a brown oil (35 mg, 23% yield).LC-MS: Rt 0.66 min; MS m/z 320.2 [M+2]+[Method A]. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.99 (d, J=7.07 Hz, 2H), 2.11-2.22 (m, 1H), 1.44-1.52 (m,2H), 1.07 (s, 6H), 0.98 (s, 6H), 0.82 (t, J=12.38 Hz, 2H).

Step 3:2-(2-Methoxy-4-(1H-pyrazol-1-yl)phenyl)-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole

To a stirred suspension of1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazole[Intermediate 4] [39 mg, 0.128 mmol) and2-bromo-5-((2,2,6,6-tetramethylpiperidin-4-yl)methyl)-1,3,4-thiadiazole(34 mg, 0.107 mmol) in dioxane (1 mL) was added Pd(PPh₃)₄ (6 mg, 0.005mmol), followed by a solution of Na₂CO₃ (34 mg, 0.32 mmol) in water(0.25 mL). The reaction mixture was purged with nitrogen, sealed, andheated at 120° C. for 1 hour under microwave irradiation. The reactionmixture was diluted with DCM (20 mL) and washed with saturatedNaHCO_(3(aq)) (10 mL). The organic phase was separated and concentratedin vacuo to afford the crude product as a brown oily residue. The crudematerial was purified by UV directed preparative HPLC under acidicconditions (formic acid modified) and the product containing fractionswere loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridgewas washed with MeOH (10 mL) then flushed with 7M NH₃ in MeOH (10 mL).The MeOH/NH₃ was removed in vacuo to afford the title compound as aslightly off-white solid 28.6 mg, 65% yield). LC-MS: Rt 0.88 min; MS m/z412.5 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.70 (d, J=2.53Hz, 1H), 8.39 (d, J=8.59 Hz, 1H), 7.83 (d, J=1.01 Hz, 1H), 7.73 (d,J=1.52 Hz, 1H), 7.67 (dd, J=8.59, 2.02 Hz, 1H), 6.64-6.61 (m, 1H), 4.11(s, 3H), 3.01 (d, J=6.57 Hz, 2H), 2.17-2.28 (m, 1H), 1.53 (dd, J=12.63,2.53 Hz, 2H), 1.09 (s, 6H), 1.00 (s, 6H), 0.86 (t, J=12.38 Hz, 2H).

Example 99 Synthesis of2-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole

Step 1: tert-Butyl2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A stirred suspension of 2,5-dibromo-1,3,4-thiadiazole (245 mg, 1.004mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (290 mg, 1.105mmol) and DIPEA (702 μL, 1.02 mmol) in dioxane (2.5 mL) was heated at120° C. for 1 hour. The reaction mixture was diluted with water (10 mL),extracted with DCM (20 mL), and the organic phase was concentrated ontosilica gel. The crude material was purified by flash chromatographyusing a 24 g silica cartridge running an EtOAc/heptane gradient toafford the title compound as a yellow oil (343 mg, 88% yield). LC-MS: Rt1.25 min; MS m/z 391.2 [M+2]⁺ [Method A]. ¹H NMR (400 MHz, Chloroform-d)δ 3.87 (s, 4H), 3.34-3.43 (m, 4H), 1.73-1.85 (m, 4H), 1.46 (s, 9H).

Step 2: tert-Butyl2-(5-(4-(benzyloxy)-2,3-difluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Nitrogen was bubbled through a stirred solution of(4-(benzyloxy)-2,3-difluorophenyl)boronic acid (356 mg, 1.349 mmol) andtert-butyl2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(343 mg, 0.881 mmol) in dioxane (8 mL). To this solution was addedPd(PPh₃)₄ (52 mg, 0.045 mmol) followed by a solution of Na₂CO₃ (286 mg,2.7 mmol) in water (2 mL). The reaction mixture was sealed and heated at100° C. for 1 hour under microwave irradiation. The reaction mixture wasdiluted with EtOAc (150 mL) and washed with water (75 mL). The organicphase was separated, dried over MgSO₄, and filtered. The filtrate wasconcentrated in vacuo to afford the crude product as a lightorange/brown solid. The crude material was pre-absorbed onto silica geland purified by flash chromatography using a 40 g silica cartridgerunning an EtOAc/heptane gradient to afford the title compound as awhite solid (169 mg, 35% yield). LC-MS: Rt 1.62 min; MS m/z 529.4 [M+H]⁺[Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ 7.75-7.82 (m, 1H), 7.46-7.51 (m,2H), 7.36-7.45 (m, 3H), 7.24-7.32 (m, 1H), 5.30 (s, 2H), 3.89 (s, 4H),3.24-3.31 (m, 4H), 1.66-1.78 (m, 4H), 1.40 (s, 9H).

Step 3: tert-Butyl2-(5-(2,3-difluoro-4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A suspension of tert-butyl2-(5-(4-(benzyloxy)-2,3-difluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(169 mg, 0.32 mmol) in a 1:3 mixture of MeOH:EtOAc (12 mL) was added toa nitrogen flushed flask containing 10% Pd/C (17 mg). The reactionmixture was placed under hydrogen atmosphere (50 psi) on a Parr shakerfor 18 hours. Additional 10% Pd/C (169 mg) was added and the reactionwas re-subjected to hydrogenation at 50 psi using a Parr shaker for afurther 5 days. The reaction mixture was placed under an inertatmosphere (nitrogen), diluted with 10% MeOH/DCM (50 mL), filteredthrough celite, and rinsed with DCM. The filtrate was concentrated invacuo to afford a pale brown solid which was re-dissolved in a 1:1mixture MeOH:DCM (8 mL) and re-subjected to hydrogenation for 4 days at50 psi using a Parr shaker and 10% Pd/C (169 mg) as the catalyst. Thereaction mixture was diluted with 10% MeOH/DCM (50 mL), filtered throughcelite, and rinsed with DCM. The filtrate was concentrated in vacuo toafford the crude product as a slightly off-white solid. The crudematerial was purified by flash chromatography using a 12 g silicacartridge running a MeOH/DCM gradient to afford the title compound as anoff-white solid (47 mg, 34% yield). LC-MS: Rt 1.27 min; MS m/z 439.3[M+H]+[Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.65 (td,J=8.5, 2.2 Hz, 1H), 6.92 (td, J=8.5, 1.9 Hz, 1H), 3.87 (s, 4H),3.20-3.31 (m, 4H), 1.67-1.78 (m, 4H), 1.40 (s, 9H).

Step 4: tert-Butyl2-(5-(2,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A stirred solution of tert-butyl2-(5-(2,3-difluoro-4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(59 mg, 1.35 mmol) and TEA (47 μl, 0.366 mmol) in DCM (1.3 mL) undernitrogen was cooled in an ice bath. To this solution was added1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(51 mg, 0.141 mmol). The reaction mixture was stirred at ice bathtemperature for 10 minutes then warmed to room temperature for 18 hours.A further 0.5 eq of1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(24 mg, 0.067 mmol) was added and the reaction mixture was stirred foran additional 3 hours. The reaction mixture was diluted with DCM (20 mL)and washed with saturated NaHCO_(3(aq)) (10 mL). The organic phase wasseparated and concentrated in vacuo to afford the crude product as aslightly off-white solid. The crude material was purified by flashchromatography using a 12 g silica cartridge running an EtOAc/heptanegradient to afford the title compound as a white solid (68 mg, 89%yield). LC-MS: Rt 1.63 min; MS m/z 571.3 [M+H]⁺ [Method A]. ¹H NMR (400MHz, Chloroform-d) δ 8.12 (ddd, J=9.4, 7.1, 2.5 Hz, 1H), 7.25-7.21 (m,1H), 3.97 (s, 4H), 3.36-3.47 (m, 4H), 1.77-1.89 (m, 4H), 1.47 (s, 9H).

Step 5: tert-Butyl2-(5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A mixture of tert-butyl2-(5-(2,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(68 mg, 0.119 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (35 mg,0.179 mmol) in dioxane (1 mL) was stirred under nitrogen atmosphere. Tothis suspension was added Pd(PPh₃)₄ (7 mg, 0.006 mmol) followed by asolution of Na₂CO₃ (38 mg, 0.358 mmol) in water (0.25 mL). The reactionmixture was sealed and heated at 120° C. for 1 hour under microwaveirradiation. The reaction mixture was diluted with water (10 mL) andextracted with DCM (20 mL). The organic phase was separated andconcentrated in vacuo to afford the crude product as an off-white solid.The crude material was purified by UV directed preparative HPLC underbasic conditions (NH₄OH modified) to afford he title compound as a whitesolid (11 mg, 19% yield). MS m/z 489.1 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆)δ 13.30 (s, 1H), 8.18 (s, 2H), 7.85 (ddd, J=8.6, 6.7, 1.8 Hz, 1H), 7.70(ddd, J=8.7, 7.0, 1.8 Hz, 1H), 3.91 (s, 4H), 3.28-3.31 (m, 4H), 1.74 (t,J=5.6 Hz, 4H), 1.40 (s, 9H).

Step 6:2-(2,3-Difluoro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazoleHydrochloride Salt

HCl (4M solution in dioxane, 113 μL, 0.45 mmol) was added to a stirredsuspension of tert-butyl2-(5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(11 mg, 0.023 mmol) in dioxane (1 mL). The reaction mixture was stirredat room temperature for 18 hours then diluted with a roughly 1:1 mixtureof MeOH:DCM (10 mL) and a drop of water was added. The resultingsuspension was solubilized by addition of DMSO (5 mL) and the solutionwas loaded onto a 0.5 g SCX cartridge (pre-wet with MeOH). The cartridgewas washed with MeOH (10 mL) then flushed with 10% DCM in [7M NH₃ inMeOH](10 mL). The DCM/MeOH/NH₃ was removed in vacuo to afford the titlecompound as an off-white solid (7.4 mg, 85% yield). LC-MS: Rt 0.66 min;MS m/z 389.2 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) 13.30 (s, 1H),8.18 (s, 2H), 7.84 (ddd, J=8.6, 6.8, 1.7 Hz, 1H), 7.70 (ddd, J=8.6, 7.1,1.7 Hz, 1H), 3.87 (s, 4H), 2.65 (t, J=5.0 Hz, 4H), 1.70 (t, J=5.4 Hz,4H).

Example 100 Synthesis of2-(5-(2,7-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-3-fluoro-5-(1H-pyrazol-4-yl)phenol

Step 1: 5-(4-Bromo-2,6-difluorophenyl)-1,3,4-thiadiazol-2-amine

A stirred mixture of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.1 mmol)and hydrazinecarbothioamide (2.88 g, 31.6 mmol) was cooled undernitrogen in an ice bath. POCl₃ (5.9 mL, 63.3 mmol) was added drop-wiseand the reaction was stirred at ice bath temperature for 15 minutes thenheated at 78° C. for 3 hours. The reaction mixture was cooled in an icebath then quenched by addition of ice water (150 mL). The resultingsolid was sonicated for 30 minutes to give a free stirring suspensionwhich was left to slurry at room temperature for 72 hours. The solid wascollected by vacuum filtration, rinsed with water, and re-suspended insaturated NaHCO_(3(aq)) (150 mL). This suspension was stirred at roomtemperature for 18 hours then the solid was collected by vacuumfiltration, rinsed with water, and dried in a vacuum oven for 24 hoursto give the title compound (5.174 g, 84% yield) which was used in thenext step without further purification. LC-MS: Rt 0.99 min; MS m/z 294.2[M+2]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.68 (d, J=8.08 Hz,2H), 7.57 (s, 2H).

Step 2:5-(2-(Benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-amine

A stirred suspension of NaH (60% dispersion in mineral oil, 151 mg, 3.77mmol) in THF (10 mL) was cooled under nitrogen in an ice bath. To thissuspension was added a solution of benzyl alcohol (0.372 mL, 3.59 mmol)in THF (5 mL) drop-wise. On completion of addition, the resultingsuspension was stirred at ice bath temperature for 5 minutes, then roomtemperature for 10 minutes, before being slowly added to a stirred,ice-bath cooled suspension of5-(4-bromo-2,6-difluorophenyl)-1,3,4-thiadiazol-2-amine (1 g, 3.42 mmol)in THF (20 mL). The resulting yellow/brown suspension was stirred at icebath temperature for 15 minutes, room temperature for 1 hour then heatedat 50° C. for 18 hours. The reaction was quenched by addition ofsaturated NH₄Cl_((aq)) (30 mL), diluted with water (30 mL), andextracted with EtOAc (100 mL). The organic phase was separated, driedover MgSO₄, and filtered. The filtrate was concentrated onto silica geland the crude material was purified by flash chromatography using an 80g silica cartridge running an EtOAc/heptane gradient to afford the titlecompound as a pale yellow solid (488 mg, 37% yield). LC-MS: Rt 1.19 min;MS m/z 282.0 M⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ 7.27-7.47 (m,9H), 5.28 (s, 2H).

Step 3:2-(2-(Benzyloxy)-4-bromo-6-fluorophenyl)-5-bromo-1,3,4-thiadiazole

5-(2-(Benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-amine (487mg, 1.281 mmol) was added portion-wise to a stirred solution of CuBr₂(343 mg, 1.537 mmol) and t-BuNO₂ (226 μL, 1.921 mmol) in MeCN (4.2 mL)under nitrogen. The reaction mixture was stirred at room temperature for18 hours. The reaction was quenched by addition of water (40 mL), then28% NH₄OH_((aq)) (5 mL) was added, and the resulting suspension wasextracted with DCM (50 mL). The organic phase was separated andconcentrated onto silica gel. The crude material was purified by flashchromatography using a 40 g silica cartridge running an EtOAc/heptanegradient to afford the title compound as a white solid (253 mg, 44%yield). LC-MS: Rt 1.53 min; MS m/z 445.0 [M+H]+[Method A]. ¹H NMR (400MHz, DMSO-d₆) δ 7.31-7.56 (m, 7H), 5.38 (s, 2H).

Step 4: tert-Butyl2-(5-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

To a stirred suspension of2-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-5-bromo-1,3,4-thiadiazole (252mg, 0.567 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylatehydrochloride (179 mg, 0.681 mmol) in dioxane (2.8 mL) was added TEA(237 μL, 1.702 mmol) and the mixture was heated at 120° C. for 3 hours.The reaction mixture was cooled to RT, diluted with water (20 mL),extracted with DCM (20 mL). The organic phase was concentrated in vacuoto afford the crude product as a yellow oily residue. The crude materialwas purified by flash chromatography using a 40 g silica cartridgerunning an EtOAc/heptane gradient to afford the title compound as awhite solid (150 mg, 45% yield). LC-MS: Rt 1.62 min; MS m/z 591.3[M+H]+[Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ 7.29-7.47 (m, 7H), 5.31(s, 2H), 3.83 (s, 4H), 3.17-3.30 (m, 4H), 1.65-1.77 (m, 4H), 1.40 (s,9H).

Step 5: tert-Butyl2-(5-(2-(benzyloxy)-6-fluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A mixture of tert-butyl2-(5-(2-(benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(150 mg, 0.254 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg,0.382 mmol) in dioxane (2 mL) was stirred under nitrogen atmosphere. Tothis suspension was added Pd(PPh₃)₄ (15 mg, 0.013 mmol) followed by asolution of Na₂CO₃ (81 mg, 0.763 mmol) in water (0.5 mL). The reactionmixture was sealed and heated at 120° C. for 1 hour under microwaveirradiation. A further 1.5 eq of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg,0.382 mmol) was added and the reaction was heated for an additional hourat 120° C. under microwave irradiation. A further 1.5 eq of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (74 mg,0.382 mmol) was added, followed by an additional 0.05 eq of Pd(PPh₃)₄(15 mg, 0.013 mmol) and the reaction mixture was heated for 1 hour at120° C. under microwave irradiation. The reaction mixture was dilutedwith water (15 mL) and extracted with DCM (20 mL). The organic phase wasconcentrated in vacuo to afford the crude product as a pale brown oil.The crude material was purified by flash chromatography using a 24 gsilica cartridge running a MeOH/DCM gradient to afford a pale brown oil.The oil was purified using a 24 g silica running an EtOAc/heptanegradient to afford the title compound as a clear glass-like solid (86mg, 58% yield). MS m/z 577.2 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 13.10(s, 1H), 8.39 (d, J=1.8 Hz, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.47-7.57 (m,2H), 7.33-7.44 (m, 4H), 7.28 (dd, J=11.6, 1.5 Hz, 1H), 5.35 (s, 2H),3.82 (s, 4H), 3.18-3.32 (m, 4H), 1.63-1.77 (m, 4H), 1.40 (s, 9H).

Step 6: tert-Butyl2-(5-(2-fluoro-6-hydroxy-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A solution of tert-butyl2-(5-(2-(benzyloxy)-6-fluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(86 mg, 0.149 mmol) in a 1:1: mixture MeOH:DCM (3 mL) was added to anitrogen flushed flask containing 10% Pd/C (8.6 mg). The reactionmixture was placed under a hydrogen atmosphere (balloon) and stirred atroom temperature for 18 hours. The reaction mixture was flushed withnitrogen and an additional 8.6 mg of 10% Pd/C was added. The reactionwas diluted with 1:1 MeOH:DCM (3 mL), and again placed under a hydrogenatmosphere (balloon) and stirred at room temperature for an additional 5days. The reaction mixture was flushed with nitrogen, diluted with 10%MeOH in DCM (50 mL) and filtered through celite. The filtrate wasconcentrated in vacuo to afford a pale brown/off-white solid. The solidwas re-dissolved in 25% MeOH in DCM (10 mL) and added to a nitrogenflushed flash containing 10% Pd/C (8.6 mg). The reaction mixture wasplaced under a hydrogen atmosphere (balloon) and left to stir at roomtemperature for 18 hours. The reaction mixture was diluted with 10% MeOHin DCM (50 mL) and filtered through celite. The filtrate wasconcentrated in vacuo to afford the crude product as a brown solid. Thecrude material was purified by flash chromatography using a 10 g silicacartridge running a MeOH/DCM gradient and collecting by mass to affordan the title compound as a pale brown solid (54 mg, 74% yield). LC-MS:Rt 1.33 min; MS m/z 487.3 [M+H]⁺ [Method A]. ¹H NMR (400 MHz, DMSO-d₆) δ13.09 (s, 1H), 11.92 (s, 1H), 8.36 (d, J=1.7 Hz, 1H), 8.04 (d, J=1.9 Hz,1H), 7.22 (dd, J=12.6, 1.6 Hz, 1H), 7.14-7.19 (m, 1H), 3.92 (s, 4H),3.28-3.31 (m, 4H), 1.69-1.79 (m, 4H), 1.40 (s, 9H).

Step 7:2-(5-(2,7-Diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazol-2-yl)-3-fluoro-5-(1H-pyrazol-4-yl)phenol

HCl (4M solution in dioxane, 545 μL, 2.179 mmol) was added to a stirredsuspension of tert-butyl2-(5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate(53 mg, 0.109 mmol) in dioxane (4 mL). The reaction mixture was stirredat room temperature for 2 hours then diluted with dioxane (2 mL), MeOH(5 mL), DMSO (5 mL) and a small amount of water, then loaded onto a 2 gSCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH(15 mL) then flushed with 10% DCM in [7M NH₃ in MeOH](20 mL). TheDCM/MeOH/NH₃ was removed in vacuo to afford the crude product as a brownsolid. The crude material was heated in MeOH (5 mL) and the resultingsuspension was cooled to room temperature then filtered under vacuum andrinsed with MeOH to afford the title compound as a pale brown solid (23mg, 55% yield). LC-MS: Rt 0.68 min; MS m/z 387.2 [M+H]⁺ [Method A]. ¹HNMR (400 MHz, DMSO-d₆) δ 13.07 (s, 1H), 8.17 (s, 2H), 7.15-7.05 (m, 2H),3.87 (s, 4H), 2.70 (t, J=5.1 Hz, 4H), 1.73 (t, J=5.3 Hz, 4H).

Example 101 Synthesis of4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one

Step 1: 3-Bromo-4-methoxy-1-methylquinolin-2(1H)-one

To a solution of 4-methoxy-1-methylquinolin-2(1H)-one (2 g, 10.57 mmol)in THF (5 mL) at 0° C. under N₂ atmosphere was added N-bromosuccinimide(2.26 g, 12.68 mmol) in portions over a period of 1 hour. The suspensionwas stirred at 0° C. for 1 hour then at room temperature for 2 hours.The solvent was removed in vacuo and CH₂Cl₂ was added to re-dissolve theresidue. The solution was washed twice with a cold saturated NaHCO₃solution and with cold H₂O then dried over anhydrous MgSO₄. The solventwas removed in vacuo and the resulting solid residue was trituratedseveral times with Et₂O. The resulting solid was dried in vacuo toafford 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one (2.7 g, MS: 269.9[M+H⁺].) Step 2:(4-Methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid

To a solution of 3-bromo-4-methoxy-1-methylquinolin-2(1H)-one (2.7 g,10.07 mmol) in THF (5 mL) was added n-butyllithium (2.5 M in Hexane,4.03 mL) under nitrogen atmosphere at −78° C. and the reaction mixturewas maintained at this temperature for 1 h. A cooled solution oftrimethyl borate (1.35 mL, 12.08 mmol) was added at ˜78° C., and thereaction mixture was maintained at this temperature for 2 h. Thereaction mixture was warmed to room temperature and stirred overnight.The reaction mixture was diluted with 1M HCl and a white solidprecipitated from the solution. The precipitate was filtered, washedwith water and EtOAc, then dried under high vacuum to provide(4-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (1.5 g,MS: 234.1 [M+H⁺].)

Step 3:4-Methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one

A degassed reaction mixture of(4-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (500 mg,2.15 mmol),5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(858 mg, 2.57 mmol), tetrakis(triphenylphosphine)palladium(0) (248 mg,0.215 mmol) and Na₂CO₃ (682 mg, 6.44 mmol) in 1,4-dioxane (5 mL) andwater (1 mL) was heated via microwave irradiation at 100° C. for 1 h.After cooling to room temperature, the mixture was filtered throughcelite, washed with MeOH then the filtrate was concentrated. The residuewas purified by silica gel chromatography (2%˜10% 2M NH₃ in MeOH/DCM) togive4-methoxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one(240 mg, MS: 442.1 [M+H⁺].) (4 mg, MS: 442.0 [M+H⁺], LCMS Rt=1.25 min(LCMS method D); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.55 (s, 1H), 8.14(dd, J=8.08, 1.52 Hz, 1H), 7.72-7.81 (m, 1H), 7.61-7.69 (m, 1H),7.33-7.45 (m, 1H), 4.61 (br. s., 1H), 3.94 (s, 3H), 3.78 (s, 3H), 3.11(s, 3H), 1.95 (d, J=12.13 Hz, 2H), 1.79 (br. s., 2H), 1.50 (s, 6H), 1.39(br. s., 6H).

Example 102 Synthesis of4-hydroxy-1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one

By employing the methods of Example 15, Example 101 was reacted withPhSH to provide5-(1H-imidazole-1-yl)-2-(6-(methyl(2,2,6,6-tetramethyl-piperidin-4-yl)amino-)pyridazin-3-yl)phenolas a pale yellow powder (2 mg, MS: 428.2 [M+H⁺], LCMS Rt=0.57 min (LCMSmethod D); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.22 (d, J=8.08 Hz, 1H),7.68 (t, J=8.08 Hz, 1H), 7.53 (d, J=8.59 Hz, 1H), 7.31 (t, J=7.33 Hz,1H), 4.38 (br. s., 1H), 3.72 (s, 3H), 3.07 (s, 3H), 1.80 (dd, J=12.63,3.03 Hz, 2H), 1.52-1.65 (m, 2H) 1.37 (s, 6H) 1.23-1.29 (m, 6H).

Example 103 Synthesis of3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one

Step 1: (2-Oxo-1,2-dihydroquinolin-3-yl)boronic acid

To a microwave vial was added 3-bromo-2-hydroxyquinoline (50 mg, 0.223mmol), bis(pinacolato)diboron (113 mg, 0.446 mmol), potassium acetate(66 mg, 0.669 mmol), PdCl₂(dppf). CH₂Cl₂ (18.22 mg, 0.022 mmol), anddppf (12.37 mg, 0.022 mmol), followed by addition of 1,4-dioxane (6 mL).The reaction mixture was purged with N₂ and stirred under N₂ atmosphereat 90° C. overnight. The reaction mixture was filtered through adisposable filter funnel, concentrated in vacuo, and purified by silicagel chromotography (10% to 60% EtOAc in heptane) to afford(2-oxo-1,2-dihydroquinolin-3-yl)boronic acid (30 mg, MS: 190.1 [M+H⁺].)

Step 2:3-(5-(Methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one

Following a similar procedure as described for Step 3 in Example 101,(2-oxo-1,2-dihydroquinolin-3-yl)boronic acid and5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(858 mg, 2.57 mmol) were reacted to provide the crude product, which waspurified by preparative HPLC under basic condition to give3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one(14 mg, MS: 398.2 [M+H⁺], LCMS Rt=0.51 min (LCMS method D); ¹H NMR (400MHz, METHANOL-d₄) δ ppm 8.74 (s, 1H), 7.67-7.80 (m, 1H), 7.47-7.57 (m,1H), 7.31 (d, J=8.08 Hz, 1H), 7.19-7.27 (m, 1H), 4.34 (br. s., 1H), 2.99(s, 3H), 1.71 (dd, J=12.63, 3.03 Hz, 2H), 1.50 (t, J=12.38 Hz, 2H), 1.28(s, 6H), 1.10-1.23 (m, 6H).

Example 104 Synthesis of 1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one

Step 1: 3-Bromo-1-methylquinolin-2(1H)-one

To a solution of 3-bromo-2-hydroxyquinoline (50 mg, 0.223 mmol) in DMF(1 mL) was added methyl iodide (0.017 mL, 0.268 mmol) and potassiumcarbonate (46.3 mg, 0.335 mmoL) at room temperature. The reactionmixture was stirred for 16 hours at room temperature. Water was addedand the solution was extracted with ethyl acetate. The organic layer waswashed with water then aqueous saturated sodium chloride solution. Theorganic layer was dried over sodium sulfate, filtered, and concentratedin vacuo. The resulting residue was purified by silica gel columnchromatography (developing solvent: hexane/ethyl acetate=/1) to give3-bromo-1-methylquinolin-2(1H)-one (52 mg, MS: 238.1 [M+H⁺].)

Step 2:1-Methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-one

By employing the methods of Example 103,1-methyl-3-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)quinolin-2(1H)-onewas obtained as a pale yellow powder (28 mg, MS: 412.2 [M+H⁺], LCMSRt=0.62 min (LCMS method D); ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.85(s, 1H), 7.90 (d, J=7.58 Hz, 1H), 7.73-7.81 (m, 1H), 7.66-7.72 (m, 1H),7.42 (t, J=7.58 Hz, 1H), 4.73-4.84 (m, 1H), 3.88 (s, 3H), 3.10-3.19 (m,3H), 2.07 (dd, J=13.64, 3.54 Hz, 2H), 1.96 (t, J=12.88 Hz, 2H),1.61-1.69 (m, 6H), 1.46-1.57 (m, 6H).

Example 105 Synthesis of2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazoleHydrochloride Salt

Step 1: 5-(4-Bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine

To an ice-cooled mixture of 4-bromo-2-chlorobenzoic acid (3 g, 12.74mmol) and hydrazinecarbothioamide (2.17 g, 23.81 mmol) was addedphosphorous oxychloride (3.56 mL, 38.2 mmol) slowly. The mixture washeated at 78° C. overnight. After cooling to 0° C., ice water was added.The mixture was vigorously stirred for 1 h. The resulting precipitatewas filtered and washed with water then re-suspended in a saturatedNaHCO₃ solution and water (1:1) for 1 h. The solid was filtered, washedwith water, and concentrated in vacuo to give5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (2.4 g, MS: 291.8[M+H⁺].)

Step 2: 5-(2-Chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine

To a microwave vial was added5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazol-2-amine (500 mg, 1.721mmol), 4-pyrazole boronic acid pinacle ester (668 mg, 3.44 mmol), cesiumcarbonate (1.68 g, 5.16 mmol), Pd₂(dba)₃.CH₂Cl₂ (178 mg, 0.172 mmol),and Xphos (82 mg, 0.172 mmol), followed by addition of 1,4-dioxane (2mL)/H₂O (0.5 mL). The vial was purged with N₂ 3 times and the reactionmixture was heated via microwave irradiation at 100° C. for 1 h. Thereaction mixture was filtered through a disposable filter funnel, washedwith EtOAc, concentrated in vacuo, and purified by silica gelchromotography (2% to 15% MeOH/DCM) to afford5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine (250 mg,MS: 278.0 [M+H⁺].)

Step 3: (3aR,6aS)-tert-Butyl5-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

5-(2-Chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-amine (250 mg,0.9 mmol) was added, portion-wise over about 5 minutes, to a stirredsolution of CuBr₂ (241 mg, 1.08 mmol) and tert-butyl nitrite (139 mg,1.35 mmol) in MeCN (5 mL) under nitrogen atmosphere. On completion ofthe addition, the reaction mixture was left to stir at room temperaturefor 18 hours. The reaction mixture was quenched by addition of saturatedNH₄Cl_((aq)) and extracted with EtOAc. The organic phase was separatedand concentrated in vacuo to afford2-bromo-5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole a brownsolid, which was used without further purification. A degassed reactionmixture of2-bromo-5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (40 mg,0.117 mmol), cis-2-boc-hexahydropyrollo[3,4-c]pyrrole (24.86 mg, 0.117mmol), potassium fluoride (7.48 mg, 0.129 mmol), 18-crown-6 (30.9 mg,0.117 mmol) and DIEA (0.041 ml, 0.234 mmol) in NMP (1 mL) was heatedunder microwave irradiation at 190° C. for 1 h. After cooling to RT, themixture was filtered through celite, washed with MeOH, and the filtratewas concentrated. The residue was dissolved in DMSO and purified bypreparative HPLC under basic conditions to give (3aR,6aS)-tert-butyl5-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(10 mg, MS: 473.0 [M+H⁺].)

Step 4:2-(2-Chloro-4-(1H-pyrazol-4-yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4-thiadiazoleHydrochloride Salt

A solution of (3aR,6aS)-tert-butyl5-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(10 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was treated with 4M HCl indioxane (1 mL) and stirred at room temperature for 3 h. The reactionmixture was concentrated in vacuo to give the title compound (2 mg, MS:373.1 [M+H⁺], LCMS Rt=0.44 min (LCMS method D); ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 7.99 (br. s., 2H), 7.92 (d, J=8.59 Hz, 1H), 7.71 (d,J=2.02 Hz, 1H), 7.53-7.60 (m, 1H), 3.68 (dd, J=10.86, 7.83 Hz, 2H), 3.36(dd, J=10.86, 3.28 Hz, 2H), 3.03-3.11 (m, 2H), 2.97-3.03 (m, 2H), 2.75(dd, J=11.12, 3.03 Hz, 2H).

By employing similar methods as described for the preparation of Example105, using appropriate starting materials, the following compounds wereprepared:

LCMS M + 1, Rt, Example Compound Method ¹H NMR 400 MHz 106

401.1, 0.47 min, D METHANOL-d₄ δ ppm 7.99 (br. s., 2H) 7.92 (d, J = 8.08Hz, 1H) 7.70 (d, J = 1.52 Hz, 1H) 7.56 (dd, J=8.08, 1.52 Hz, 1H) 3.49-3.58 (m, 2H) 3.45 (d, J = 10.11 Hz, 1H) 3.28 (d, J = 10.61 Hz, 1H)2.60-2.75 (m, 4H) 1.98 (dt, J = 13.01, 6.38 Hz, 1H) 1.86 (dt, J = 12.76,7.77 Hz, 1H) 1.48- 1.66 (m, 4H) 2-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[4.5]decan-2-yl)- 1,3,4-thiadiazole•Hydrochloride Salt107

377.1, 0.41 min, D METHANOL-d₄ δ ppm 8.00 (br. s., 2H) 7.91 (d, J = 8.08Hz, 1H) 7.72 (d, J = 2.02 Hz, 1H) 7.57 (dd, J = 8.34, 1.77 Hz, 1H) 3.74-3.90 (m, 2H) 3.52 (d, J = 5.56 Hz, 1H) 3.47-3.51 (m, 2H) 2.99- 3.06 (m,1H) 2.91-2.99 (m, 1H) 2.84-2.90 (m, 2H) (R)-(4-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4- thiadiazol-2-yl)piperazin-2-yl)methanol•Hydrochloride Salt

Example 108 Synthesis of2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)benzo[b]thiophene-5-carbonitrile

In a microwave vial, a mixture of5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4, 150 mg, 0.450 mmol),(5-cyanobenzo[b]thiophen-2-yl)boronic acid (128 mg, 0.630 mmol) andsodium carbonate (119 mg, 1.125 mmol) in 4:1 dimethoxyethane/water (3.7mL) was degassed for 5 minutes.

Tetrakis(triphenylphosphine)palladium(0) (52.0 mg, 0.045 mmol) was addedand the mixture was heated under microwave irradiation at 140° C. for0.5 h. The mixture was partitioned between DCM and water then extractedwith DCM (4×). The DCM extracts were acidified by addition of HCl indioxane (4.0 M solution, 113 μl, 0.450 mmol) and concentrated todryness. SCX purification (1 g column, 7 M ammonia in MeOH elution),followed by flash column chromatography (4 g silica gel, 1-20% 7 Nammonia in MeOH gradient, in DCM) provided2-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)benzo[b]thiophene-5-carbonitrile(49 mg) as a light yellow solid. LC/MS Rt=0.52 min. MS=412.1 (M+1)[Method D]. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.27 (d, J=1.0 Hz, 1H),8.11 (d, J=8.6 Hz, 1H), 7.82 (s, 1H), 7.68 (dd, J=8.6, 1.5 Hz, 1H), 4.43(t, J=12.4 Hz, 1H), 3.12 (s, 3H), 1.82 (dd, J=12.6, 3.0 Hz, 2H), 1.60(t, J=12.1 Hz, 2H), 1.37 (s, 6H), 1.25 (s, 6H).

Example 109 Synthesis of5-(3-chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

Step 1:5-(Benzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

5-Bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(Intermediate 4, 150 mg, 0.450 mmol) was coupled withbenzo[b]thiophen-2-ylboronic acid (112 mg, 0.630 mmol) using the methodof Example 108 for Suzuki coupling. SCX purification (2 g column, 7 Mammonia in MeOH elution) followed by flash column chromatography (12 gsilica gel, 1-20% gradient of 3.5 M ammonia in methanol, in DCM)provided5-(benzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amineas a light yellow solid (48 mg). MS=387.0 (M+1). ¹H NMR (400 MHz,METHANOL-d₄) δ ppm 7.82-7.95 (m, 2H), 7.72 (s, 1H), 7.37-7.46 (m, 2H),4.40 (t, J=12.4 Hz, 1H), 3.11 (s, 3H), 1.82 (dd, J=12.6, 3.5 Hz, 2H),1.59 (t, J=12.4 Hz, 2H), 1.37 (s, 6H), 1.25 (s, 6H).

Step 2:5-(3-Chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

A mixture of5-(benzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine(37 mg, 0.096 mmol) and N-chlorosuccinimide (15.34 mg, 0.115 mmol) inDCE:AcOH (1:1) (1 mL) was heated at 90° C. for six hours. The reactionwas cooled to RT, diluted with saturated sodium bicarbonate, extractedwith ethyl acetate (3×), and DCM (2×). The combined organic extractswere washed with brine, dried over magnesium sulfate and concentrated toa crystalline yellow solid. Purification by flash column chromatography(4 g silica gel, 1-17% 3.5 N ammonia in MeOH gradient in DCM over 30column volumes) provided5-(3-chlorobenzo[b]thiophen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amineas a yellow solid (18 mg). LC/MS Rt=0.58 min. MS=420.9 (M−1). ¹H NMR(400 MHz, METHANOL-d₄) δ ppm 7.84-7.99 (m, 2H), 7.47-7.60 (m, 2H), 4.53(m, 1H), 3.14 (s, 3H), 1.83 (d, J=9.6 Hz, 2H), 1.55-1.68 (m, 2H), 1.38(s, 6H), 1.26 (s, 6H).

LCMS conditions:

Method A:

Waters Acquity UPLC system

Waters Acquity UPLC BEH 1.7 μm 2.1×50 mm (Part#: 186002350)

Flow rate: 1 mL/min

Temperature: 50° C. (column temp)

Mobile phase compositions:

A: Water+0.05% formic acid+3.75 mM ammonium acetate.

B: Acetonitrile+0.04% formic acid.

Gradient: (from 2 to 98% B in 1.7 min)

Method B:

Waters Acquity UPLC system

Waters Acquity BEH 1.7 μm 2.1×50 mm (Part#: 186002350)

Flow rate: 1 mL/min

Temperature: 50° C. (column temp)

Mobile phase compositions:

A: Water+3.75 mM ammonium acetate+2% ACN.

B: Acetonitrile.

Gradient: (from 2 to 98% B in 4.4 min)

Method C:

Waters Acquity G2 Xevo QTof−R₅(FWHM)>20000

Waters Acquity CSH 1.7 μm 2.1×50 mm (Part#: 186005296)

Flow rate: 1 mL/min

Temperature: 50° C. (column temp)

Mobile phase compositions:

A: Water+3.75 mM ammonium acetate+0.001% formic acid.

B: Acetonitrile.

Gradient: (from 2 to 98% B in 4.4 min)

Method D:

Waters Acquity UPLC system

Waters Acquity UPLC BEH C18 1.7 um, 2.1×30 mm (Part#: 186002349)

Flow rate: 1 mL/min

Temperature: 55° C. (column temp)

Mobile phase compositions:

A: 0.05% formic acid in water.

B: 0.04% formic acid in methanol.

Gradient:

Time (min) Flow (mL/min) % A % B 0 1.000 95.0 5.0 0.10 1.000 95.0 5.00.50 1.000 20.0 80.0 0.60 1.000 5.0 95.0 0.80 1.000 5.0 95.0 0.90 1.00095.0 5.0 1.15 1.000 95.0 5.0

Abbreviations:

~ about or to 1H NMR proton nuclear magnetic resonance Chloroform-ddeuterated chloroform; CDCl3 d doublet DCM dichloromethane DIPEA, DIEAdiisopropylethylamine DMF dimethylformamide DMSO-d6 deuterateddimethylsulfoxide DPPF 1,1′-bis(diphenylphosphino)ferrocene dtbpy4,4′-di-tert-butyl-2,2′-dipyridyl Eq, eq equivalents Et ethyl Ether,Et2O diethyl ether EtOAc ethylacetate EtOH ethanol EtONa sodium ethoxideg gram h, hr hour HPLC high performance liquid chromatography HR-MS highresolution mass spectrometry [Ir(COD)(OMe)]2(1,5-Cyclooctadiene)(methoxy)iridium(I) dimer L liter LC-MS liquidchromatography mass spectrometry LiHMDS lithium hexamethyldisilazide mmultiplet Me methyl MeCN acetonitrile Mel methyl iodide MeOD,Methanol-d4 deuterated methanol MeOH methanol MHz megahertz mLmilliliter mol mole mmol millimole mol micromole MTOMethyltrioxorhenium(VII) nBuLi n-butyl lithium nm nanometers NMPN-methylpiperidone Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)Pd/C palladium on carbon PdCl2(dppf)•CH2Cl2 [1,1′- adductBis(diphenylphosphino)ferrocene]- dichloropalladium(II), complex withdichloromethane Pd2(dba)3•CH2Cl2Tris(dibenzylideneacetone)dipalladium(0)- chloroform adduct PhSHthiophenol ppm parts per million psi pounds per square inch RT roomtemperature s singlet SCX strong cation exchange SiliaMetS DMT silicabound 2,4,6-trimercaptotriazine TBAF tetrabutylammonium fluoride TBMEtert-butyl methyl ether t-BuNO2 tert-butyl nitrite TEA triethylamine TFAtrifluoroacetic acid THF tetrahydrofuran UV ultraviolet light uWmicrowave XPhos 2-Dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl

Biological Example 1

A cellular SMN ELISA was used to measure the effects of low molecularweight compounds on SMN protein elevation. Cells from a myoblast cellline derived from the SMNdelta7 mouse model (kind gift from SteveBurden, NYU) were seeded into a 384-well plate at a density of 3000cells/well and treated with compounds for 24 hours. ELISA capture plateswere prepared by coating 384-well plates (Immulon 4HBX) with 0.5 ug/mLof anti-SMN mAb (BD Science, Catalog number 610647) at 4° C. overnight.The plates were washed 5 times with 110 uL of PBS-Tween (0.05% Tween-20,PBST), blocked with 100 uL of 1% BSA in PBST for 2 hours and washed (5times) with 100 uL of PBST. After 24 hours of compound treatment cellswere lysed in a modified RIPA-buffer, on ice for 1 hour. 20 uL of lysateand 20 uL of 1% BSA were then added to the ELISA capture plates andincubated at 4° C. overnight. Plates were washed (5 times) with PBST andthen incubated with 1:100 dilution of primary rabbit anti-SMN polyclonalantibody (Santa cruz, Catalog number SC-15320) at room temperature for 1hour and subsequently washed (5 times) with 110 uL of PBST. This wasfollowed by addition of 1:100 Goat anti-Rabbit IgG-HRP linked (CellSignaling, Catalog number 7074) secondary antibody for 1 hour. Plateswere then washed with PBST and incubated with 40 uL TMB substrate (CellSignaling, Catalog number 7004L) at room temperature for 1-10 minuteswith shaking. The reaction was stopped by addition of 40 uL of stopsolution (Cell signaling, Catalog number 7002L) and absorption wasmeasured at 450 nm. Data was reported as fold activation over DMSOcontrol and EC₅₀. ELISA assay condition: compound concentration range100 pM-10 uM.

Activity Table: ELISA data generated using Biological Example ExampleSMN Activity # Structure Chemical Name Fold, EC₅₀  1

5-(2-Methoxy-4-(1H- pyrazol-1-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.45, 63 nM  2

6-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)naphthalen-2-ol 2.66, 436 nM  3

5-(2-Methoxyquinolin-3-yl)- N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.67, 337 nM  4

5-(3-Methoxynaphthalen-2- yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.48, 887 nM  5

5-(2-Methoxy-4-(1H- pyrazol-1-yl)phenyl)-N- (1,2,2,6,6-pentamethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.88, 87 nM  6

5-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine: 2.49, 44 nM  7

5-(2-Methoxy-4-(1H- pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.86, 38 nM  8

4-(3-Methoxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin- 2(1H)-one3.20, 134 nM  9

5-(3-Methoxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2-ol 2.46, 784 nM  10

5-(3-Methoxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin- 2(1H)-one2.65, 79 nM  11

N-Methyl-5-(2-methyl-4-(1- methyl-1H-pyrazol-4- yl)phenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.84, 684 nM  12

1-Methyl-4-(4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-3- (trifluoromethoxy)phenyl)pyridin-2(1H)-one 2.20, 895 nM  13

5-(4-(3,5-Dimethyl-1H- pyrazol-4-yl)-2- methoxyphenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amineinactive  14

5-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine inactive  15

2-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1-methyl-1H-pyrazol- 4-yl)phenol3.14, 32 nM  16

2-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-1- yl)phenol 2.76, 171nM  17

5-(3-Hydroxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin- 2(1H)-one2.74, 36 nM  18

4-(3-Hydroxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin- 2(1H)-one3.36, 61 nM  19

5-(3-Hydroxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2-ol 2.85, 51 nM  20

3-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)naphthalene-2,7-diol 2.63, 48 nM  21

3-(5-((3aR,6aS)- Hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazol-2-yl)naphthalene- 2,7-diol 2.66, 323 nM  22

3-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)naphthalen-2- ol•hydrobromide salt2.70, 253 nM  23

3-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-2-ol 2.66, 231 nM  24

2-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-4-(1H-pyrazol-1- yl)phenol 2.28, 987nM  25

5-(2-Chloro-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.49, 132 nM  26

3-Chloro-2-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1-methyl-1H-pyrazol- 4-yl)phenol2.26, 3 nM  27

5-(2-chloro-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.48, 193 nM  28

3-Methoxy-2-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(5-methyloxazol-2- yl)phenol 2.70,20 nM  29

2-(2-Methoxy-4-(1H- pyrazol-1-yl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4- yl)-1,3,4-thiadiazole 2.46, 879 nM  30

2-(5-(piperazin-1-yl)-1,3,4- thiadiazol-2-yl)-5-(1H- pyrazol-1-yl)phenol1.98, 6560 nM  31

5-(7-Methoxyquinolin-6-yl)- N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.43, 113 nM  32

6-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-7-ol 2.48, 256 nM  33

3-methoxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 2.16, 1040 nM  34

3-fluoro-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzonitrile 2.32, > 10000 nM  35

methyl 3-fluoro-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzoate 2.81, 864 nM  36

5-(2-methoxy-4-(3- (methylamino)-1H-pyrazol- 1-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.15, 163nM  37

7-methoxy-6-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinoline-2-carbonitrile 2.19, 78 nM 38

4-(3-methoxy-4-(5- ((2,2,6,6- tetramethylpiperidin-4-yl)oxy)-1,3,4-thiadiazol-2- yl)phenyl)-1-methylpyridin- 2(1H)-one 2.12,1523 nM  39

4-(3-chloro-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol- 2-yl)phenyl)-1- methylpyridin-2(1H)-one2.31, 50 nM  40

5-(2-chloro-4-(1H-pyrazol- 4-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.55, 34 nM  41

5-(2-chloro-4-(4,5,6,7- tetrahydropyrazolo[1,5-a]pyridin-3-yl)phenyl)-N- methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine 2.44, 507 nM  42

N-methyl-5-(5-(1-methyl- 1H-pyrazol-4-yl)pyridin-2- yl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine. Hydrochloride salt2.32, 675 nM  43

2-(2-chloro-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-5- ((2,2,6,6-tetramethylpiperidin-4- yl)oxy)-1,3,4-thiadiazole 2.28, 446 nM  44

5-(2-chloro-4-(6- methoxypyridin-3- yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.26, 4917 nM  45

5-(4-(6-aminopyridin-3-yl)- 2-fluorophenyl)-N-methyl- N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.26, 163 nM  46

5-(2-fluoro-4-(3-methyl-1H- pyrazol-5-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.32, 122 nM  47

5-(2-fluoro-4-(1H-pyrazol- 5-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.29, 152 nM  48

5-(2,3-difluoro-4-(1H- pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 3.04, 33 nM  49

5-(2,3-difluoro-4-(1H- pyrazol-5-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.42, 81 nM  50

5-(2,5-difluoro-4-(1H- pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 3.07, 20 nM  51

5-(2,5-difluoro-4-(1H- pyrazol-5-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.86 85 nM  52

5-(2,6-difluoro-4-(1H- pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 3.30, 61 nM  53

2-(2,5-difluoro-4-(1H- pyrazol-4-yl)phenyl)-5- ((3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 2.56, 70 nM 54

5-(2-chloro-5-fluoro-4-(1H- pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 3.16, 47 nM  55

5-(3-fluoro-5-(1H-pyrazol- 4-yl)pyridin-2-yl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.75, 1011 nM  56

5-(4-(2-aminopyrimidin-4- yl)-2-chlorophenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.47, 41 nM  57

5-(5-(2-aminopyrimidin-4- yl)-2-chlorophenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.55, 94 nM  58

5-(4-(2,4-dimethylthiazol-5- yl)-2,5-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine2.41, 386 nM  59

5-(4-(2,4-dimethylthiazol-5- yl)-2,3-difluorophenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine2.69, 1501 nM  60

4-(3-hydroxy-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol- 2-yl)-5- (trifluoromethoxy)phenyl)-1-methylpyridin-2(1H)-one 2.69, 53 nM  61

5-(2-fluoro-6-methoxy-4- (1H-pyrazol-4-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.36, 95 nM  62

2-(2-fluoro-6-methoxy-4- (1H-pyrazol-4-yl)phenyl)-5- ((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 2.01,3642 nM  63

5-(2,3-difluoro-6-methoxy-4- (1H-pyrazol-4-yl)phenyl)-N-methyl-N-(2,2,6,6- tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine3.13, 47 nM  64

6-methoxy-2-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-3,4-dihydroisoquinolin- 1(2H)-one2.51, 1620 nM  65

5-(2-chloro-4-(1H-pyrazol-1- yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.37, 273 nM  66

5-(2-chloro-4-(1H-1,2,3- triazol-1-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.32, 130 nM  67

5-(2-chloro-4-(2H-1,2,3- triazol-2-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.45, 159 nM  68

5-(2-chloro-4-(1H-1,2,4- triazol-1-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.64, 79 nM  69

5-(4-(3-amino-1H-pyrazol-1- yl)-2-chlorophenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.44, 171 nM  70

2-(2-chloro-4-(1H-imidazol- 1-yl)phenyl)-5-((3aR,6aS)- 5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 2.17,2571 nM  71

5-(2-chloro-4-(1H-imidazol- 1-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.40, 32 nM  72

5-(2-fluoro-4-(1H-imidazol- 1-yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.50, 91 nM  73

5-(2-methoxy-4-(1H- pyrazol-5-yl)phenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.73, 110 nM  74

5-(4-(2,4-dimethylthiazol-5- yl)-2-methoxyphenyl)-N- methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.64, 85 nM  75

5-(2-methoxy-4-(pyridin-3- yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.44, 235 nM  76

5-(2-fluoro-4-(1H-pyrazol-4- yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 3.06, 43 nM  77

5-(2-methoxy-4-(2- methoxypyridin-4- yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 3.33, 52 nM  78

5-(2-methoxy-4-(6- methoxypyridin-3- yl)phenyl)-N-methyl-N- (2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.52, 165 nM  79

2-(2-chloro-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-5- ((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 2.76,150 nM  80

2-(2-chloro-4-(1H-pyrazol-4- yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 2.70,149 nM  81

2-(2-chloro-4-(1H-pyrazol-4- yl)phenyl)-5-((3aR,6aR)-1-methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-1,3,4- thiadiazole 2.38,1538 nM  82

1-(4-(5-(2-chloro-4-(1H- pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)morpholin-2- yl)-N,N- dimethylmethanamine 2.50, 994 nM 83

2-(2-chloro-4-(1H-pyrazol-4- yl)phenyl)-5-(2-methyl-2,7-diazaspiro[4.5]decan-7-yl)- 1,3,4-thiadiazole 2.59, 3280 nM  84

2-(2-fluoro-4-(1H-pyrazol-4- yl)phenyl)-5-((3aR,6aS)-5-methylhexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4- thiadiazole 2.11,193 nM  85

2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan- 2-yl)-1,3,4-thiadiazole 2.22, 282 nM  86

2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan- 2-yl)-1,3,4-thiadiazole 2.33, 152 nM  87

2-(5-(Methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-1- yl)phenol 2.76, 171nM  88

5-(3-chloro-4-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)phenyl)pyridin-2(1H)-one 2.22, 160 nM 89

2-(5-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(3-(methylamino)-1H-pyrazol-1-yl)phenol 2.85, 106 nM  90

3-fluoro-2-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4- yl)phenol 2.57, 6 nM 91

3,4-difluoro-2-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4- yl)phenol 2.67, 3 nM 92

6-hydroxy-5-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-2,3-dihydro-1H-inden-1- one 2.50, 91nM  93

2-(5-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4- yl)phenol 2.47, 404nM  94

2-(5-(2,6- diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)phenol 2.59, 155 nM  95

2-(5-(2,7- diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazol-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)phenol 2.44, 53 nM  96

3-fluoro-2-(5-((3aR,6aS)- hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1,3,4- thiadiazol-2-yl)-5-(1H- pyrazol-4-yl)phenol.Di- hydrochloride salt 2.85, 9 nM  97

3-chloro-2-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)-5-(1H-pyrazol-4- yl)phenol 2.45, 3 nM 98

2-(2-methoxy-4-(1H- pyrazol-1-yl)phenyl)-5- ((2,2,6,6-tetramethylpiperidin-4- yl)methyl)-1,3,4-thiadiazole 2.19, 818 nM  99

2-(2,3-difluoro-4-(1H- pyrazol-4-yl)phenyl)-5-(2,7-diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazole 100

2-(5-(2,7- diazaspiro[3.5]nonan-2-yl)- 1,3,4-thiadiazol-2-yl)-3-fluoro-5-(1H-pyrazol-4- yl)phenol 101

4-methoxy-1-methyl-3-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-2(1H)-one 2.51, 742 nM 102

4-hydroxy-1-methyl-3-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-2(1H)-one 2.71, 24 nM 103

3-(5-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-2(1H)-one 2.47, 161 nM 104

1-methyl-3-(5- (methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)quinolin-2(1H)-one 2.76, 100 nM 105

2-(2-chloro-4-(1H-pyrazol-4- yl)phenyl)-5-((3aR,6aS)-hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-1,3,4-thiadiazole•Hydrochloride Salt 2.21, 181 nM 106

2-(2-chloro-4-(1H-pyrazol-4- yl)phenyl)-5-(2,7-diazaspiro[4.5]decan-2-yl)- 1,3,4- thiadiazole•Hydrochloride Salt 2.50,1656 nM 107

(R)-(4-(5-(2-chloro-4-(1H- pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)piperazin-2- yl)methanol•Hydrochloride Salt 2.06, 4535nM 108

2-(5-(methyl(2,2,6,6- tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2- yl)benzo[b]thiophene-5- carbonitrile 2.72,539 nM 109

5-(3- chlorobenzo[b]thiophen-2- yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)- 1,3,4-thiadiazol-2-amine 2.75, 534 nM

What is claimed is:
 1. A compound, or salt thereof, which compound isrepresented by Formula (X)

wherein A′ is phenyl which is substituted with 1, 2, or 3 substituentsindependently selected from C₁-C₄alkyl, wherein 2 C₁-C₄alkyl groups cancombine with the atoms to which they are bound to form a 5-6 memberedring and is substituted with 0 or 1 substituent selected from oxo, oximeand hydroxy, haloC₁-C₄alkyl, dihaloC₁-C₄alkyl, trihaloC₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄alkoxy-C₃-C₇cycloalkyl, haloC₁-C₄alkoxy,dihaloC₁-C₄alkoxy, trihaloC₁-C₄alkoxy, hydroxy, cyano, halogen, amino,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, heteroaryl, C₁-C₄alkylsubstituted with hydroxy, C₁-C₄alkoxy substituted with aryl,—C(O)NHC₁-C₄alkyl-heteroaryl, —NHC(O)—C₁-C₄alkyl-heteroaryl,C₁-C₄alkylC(O)NH-heteroaryl, C₁-C₄alkylNHC(O)-heteroaryl, 3-7 memberedcycloalkyl, 5-7 membered cycloalkenyl and 5, 6 or 9 membered heterocyclecontaining 1 or 2 heteroatoms, independently, selected from S, O and N,wherein heteroaryl has 5, 6 or 9 ring atoms, 1, 2 or 3 ring heteroatomsselected from N, O and S, and substituted with 0, 1, or 2 substituentsindependently selected from oxo, hydroxy, nitro, halogen, C₁-C₄alkyl,C₁-C₄alkenyl, C₁-C₄alkoxy, C₃-C₇cycloalkyl, C₁-C₄alkyl-OH,trihaloC₁-C₄alkyl, mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, —C(O)NH₂,—NH₂, —NO₂, hydroxyC1-C₄alkylamino, hydroxyC₁-C₄alkyl, 4-7memberheterocycleC₁-C₄alkyl, aminoC₁-C₄alkyl, mono-C₁-C₄alkylaminoC₁-C₄alkyland di-C₁-C₄alkylaminoC₁-C₄alkyl; or A′ is 6 member heteroaryl having1-3 ring nitrogen atoms, which 6 member heteroaryl is substituted byphenyl or a heteroaryl having 5 or 6 ring atoms, 1 or 2 ring heteroatomsindependently selected from N, O and S, and substituted with 0, 1, or 2substituents independently selected from C₁-C₄alkyl,mono-C₁-C₄alkylamino, di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, mono-C₁-C₄alkylaminoC₁-C₄alkyl anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A′ is bicyclic heteroaryl having 9 to10 ring atoms and 1, 2, or 3 ring heteroatoms independently selectedfrom N, O or S, which bicyclic heteroaryl is substituted with 0, 1, or 2substituents independently selected from oxo, cyano, halogen, hydroxy,C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, C₁-C₄alkoxysubstituted with hydroxy, C₁-C₄alkoxy, amino, mono-C₁-C₄alkylamino anddi-C₁-C₄alkylamino; B is a group of the formula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄akylamino; R₅ and R₆ areindependently selected from hydrogen and fluorine; or R and R₃, taken incombination form a fused 5 or 6 member heterocyclic ring having 0 or 1additional ring heteroatoms selected from N, O or S; R₁ and R₃, taken incombination form a C₁-C₃alkylene group; R, and R₅, taken in combinationform a C₁-C₃alkylene group; R₃ and R₄, taken in combination with thecarbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; Xis CR_(A′)R_(B′), NR₇ or a bond; R₇ is hydrogen, or C₁-C₄alkyl; R_(A′)and R_(B′) are independently selected from hydrogen and C₁-C₄alkyl, orR_(A′) and R_(B′), taken in combination, form a divalent C₂-C₅alkylenegroup; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or takenin combination with R₆ form a double bond; or B is a group of theformula:

wherein Y is C or O and when Y is O R₁₁ and R₁₂ are both absent; p and qare independently selected from the group consisting of 0, 1, and 2; R₉and R₁₃ are independently selected from hydrogen and C₁-C₄alkyl; R₁₀ andR₁₄ are independently selected from hydrogen, amino, mono- anddi-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionally substitutedwith hydroxy, amino or mono- and di-C₁-C₄akylamino; R₁₁ is hydrogen,C₁-C₄alkyl, amino or mono- and di-C₁-C₄akylamino; R₁₂ is hydrogen orC₁-C₄alkyl; or R₉ and R₁₁, taken in combination form a saturatedazacycle having 4 to 7 ring atoms which is optionally substituted with1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups.
 2. A compound, or salt thereof,according to claim 1, wherein A′ is selected from:


3. A compound, or a salt thereof, according to claim 1, which compoundis represented by Formula (XX):

wherein R^(b) is hydrogen or hydroxy; R^(c) is hydrogen or halogen; andR^(d) is halogen.
 4. A compound, or salt thereof, according to claim 1,wherein B is selected from

wherein Z is NH or N(Me).
 5. A compound, or salt thereof, according toclaim 4, wherein B is


6. A compound, or salt thereof, according to claim 1, wherein B isselected from


7. A compound, or salt thereof, according to claim 6 wherein B is


8. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptablecarriers.
 9. A combination comprising a therapeutically effective amountof a compound according to claim 1 or a pharmaceutically acceptable saltthereof and one or more therapeutically active co-agents.
 10. A methodto treat or ameliorate an SMN-deficiency-related condition, comprisingadministering to a subject in need thereof an effective amount of acompound or salt thereof of claim
 1. 11. The method of claim 15, whereinsaid SMN-deficiency-related condition is Spinal Muscular Atrophy.
 12. Acompound, or salt thereof, which compound is represented by Formula (I)

wherein Y is N or C—R^(a); R^(a) is hydrogen or C₁-C₄alkyl; R^(b) ishydrogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, cyano, halogen, trihaloC₁-C₄alkyl or trihalo C₁-C₄alkoxy; R^(c) and R^(d) are each,independently, hydrogen, C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, trihaloC₁-C₄alkyl, trihalo C₁-C₄alkoxy or heteroaryl; A is 6 member heteroarylhaving 1-3 ring nitrogen atoms, which 6 member heteroaryl is substitutedwith 0, 1, or 2 substituents independently selected from oxo,C₁-C₄alkyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A is 5 member heteroaryl having 1-3ring heteroatoms independently selected from N, O and S and substitutedwith 0, 1, or 2 substituents independently selected from C₁-C₄alkyl,hydroxyl, mono- and di-C₁-C₄alkylamino, hydroxyC₁-C₄alkylamino,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl and mono- anddi-C₁-C₄alkylaminoC₁-C₄alkyl; or A and R^(c), together with the atoms towhich they are bound, form a 6 member aryl with 1, or 2 substituentsindependently selected from cyano, halogen, hydroxy, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy and C₁-C₄alkoxy substituted withhydroxy, C₁-C₄alkoxy, amino and mono- and di-C₁-C₄alkylamino; B is agroup of the formula:

wherein m, n and p are independently selected from 0 or 1; R, R₁, R₂,R₃, and R₄ are independently selected from the group consisting ofhydrogen, C₁-C₄alkyl, which alkyl is optionally substituted withhydroxy, amino or mono- and di-C₁-C₄akylamino; R₅ and R₆ areindependently selected from hydrogen and fluorine; or R and R₃, taken incombination form a fused 5 or 6 member heterocyclic ring having 0 or 1additional ring heteroatoms selected from N, O or S; R₁ and R₃, taken incombination form a C₁-C₃alkylene group; R₁ and R₅, taken in combinationform a C₁-C₃alkylene group; R₃ and R₄, taken in combination with thecarbon atom to which they attach, form a spirocyclicC₃-C₆cycloalkyl; Xis CR_(A′)R_(B′), NR₇ or a bond; R₇ is hydrogen, or C₁-C₄alkyl; R_(A′)and R_(B′) are independently selected from hydrogen and C₁-C₄alkyl, orR_(A′) and R_(B′), taken in combination, form a divalent C₂-C₅alkylenegroup; Z is CR₈ or N; when Z is N, X is a bond; R₈ is hydrogen or takenin combination with R₆ form a double bond; or B is a group of theformula:

wherein p and q are independently selected from the group consisting of0, 1, and 2; R₉ and R₁₃ are independently selected from hydrogen andC₁-C₄alkyl; R₁₀ and R₁₄ are independently selected from hydrogen, amino,mono- and di-C₁-C₄akylamino and C₁-C₄alkyl, which alkyl is optionallysubstituted with hydroxy, amino or mono- and di-C₁-C₄akylamino; R₁₁ ishydrogen, C₁-C₄alkyl, amino or mono- and di-C₁-C₄akylamino; R₁₂ ishydrogen or C₁-C₄alkyl; or R₉ and R₁₁, taken in combination form asaturated azacycle having 4 to 7 ring atoms which is optionallysubstituted with 1-3 C₁-C₄alkyl groups; or R₁₁ and R₁₂, taken incombination form a saturated azacycle having 4 to 7 ring atoms which isoptionally substituted with 1-3 C₁-C₄alkyl groups.
 13. A compound, or asalt thereof, according to claim 3, wherein A is selected from:


14. A compound, or salt thereof, according to claim 12, wherein B isselected from

wherein Z is NH or N(Me).
 15. A compound, or salt thereof, according toclaim 14, wherein B is


16. A compound, or salt thereof, according to claim 12, wherein B isselected from


17. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 12, or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptablecarriers.
 18. A combination comprising a therapeutically effectiveamount of a compound according to claim 12 or a pharmaceuticallyacceptable salt thereof and one or more therapeutically activeco-agents.
 19. A method to treat or ameliorate an SMN-deficiency-relatedcondition, comprising administering to a subject in need thereof aneffective amount of a compound or salt thereof of claim
 12. 20. Themethod of claim 19, wherein said SMN-deficiency-related condition isSpinal Muscular Atrophy.